BRIEFING

1160 Pharmaceutical Calculations in Prescription Compounding, USP 37 page

1033. It is proposed to change the title of this general information chapter to
Pharmaceutical Calculations in Pharmacy Practice 1160 . This change will provide a
better description of the contents of the revised general chapter. The proposed general
chapter is revised with new material that includes the deletion of problem types that are
no longer relevant, more practical pharmaceutical calculations and problem examples,
updated definitions, new sections, and added resources. The new information proposed
in this chapter will educate the reader on the advancements in pharmacy practice.
Additionally, minor editorial changes have been made to update the chapter to current
USP style.
The proposed chapter is posted online at www.usp.org/usp-nf/notices/GC1160-
compounding-notice with line numbers. To ensure that your comments are received and
addressed, please provide the line numbers corresponding to your comments when
submitting comments to [email protected].

(CMP: J. Sun.) Correspondence Number—C135267

Change to read:

1 1160 PHARMACEUTICAL
2 CALCULATIONS IN PRESCRIPTION
3 COMPOUNDING▪PHARMACY
4 PRACTICE▪ 1S (USP38)

5 Change to read:
6
7 INTRODUCTION
8 The purpose of this chapter is to provide general information to guide and assist
9 pharmacists in performing the necessary calculations when preparing or compounding
10 any pharmaceutical article (see Pharmaceutical Compounding—Nonsterile Preparations
11 795 , Pharmaceutical Compounding—Sterile Preparations 797 , and Good
12 Compounding Practices 1075 ) or when simply dispensing prescriptions (see Stability
13 Considerations in Dispensing Practice 1191 ).
14 Correct pharmaceutical calculations can be accomplished by using, for example, proper
15 conversions from one measurement system to another and properly placed decimal
16 points, by understanding the arithmetical concepts, and by paying close attention to the
17 details of the calculations. Before proceeding with any calculation, pharmacists should
18 do the following: (a) read the entire formula or prescription carefully; (b) determine
19 which materials are needed; and then (c) select the appropriate methods of preparation
20 and the appropriate calculation.
21 There are often several ways to solve a given problem. Logical methods that require as
22 few steps as possible should be selected in order to ensure that calculations are done
23 correctly. The best approach is the one that yields results that are accurate and free of
24 error. The pharmacist must double-check each calculation before proceeding with the
25 preparation of the article or prescription order. One way of double-checking is by
26 estimation. This involves rounding off the quantities involved in the calculation, and
27 comparing the estimated result with the calculated value.
28 Finally, the following steps should be taken: the dosage of each active ingredient in the
29 prescription should be checked; all calculations should be doubly checked, preferably
30 by another pharmacist; and where instruments are used in compounding, they should
31 be carefully checked to ascertain that they will function properly. See USP general
32 chapters Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry Powder Inhalers
33 601 , Deliverable Volume 698 , Density of Solids 699 , Osmolality and Osmolarity
34 785 , pH 791 , Pharmaceutical Compounding—Nonsterile Preparations 795 ,
35 Pharmaceutical Compounding—Sterile Preparations 797 , Viscosity 911 , Specific
36 Gravity 841 , Cleaning Glass Apparatus 1051 , Medicine Dropper 1101 ,
37 Prescription Balances and Volumetric Apparatus 1176 , Teaspoon 1221 ,
38 Weighing on an Analytical Balance 1251 , and Good Compounding Practices 1075
39 for information on specific instruments.
40
41 BASIC MATHEMATICAL CONCEPTS
42 SIGNIFICANT FIGURES
43 Expressed values are considered significant to the last digit shown (see Significant
44 Figures and Tolerances in the General Notices). Significant figures are digits with
45 practical meaning. The accuracy of the determination is implied by the number of
46 figures used in its expression. In some calculations zeros may not be significant. For
47 example, for a measured weight of 0.0298 g, the zeros are not significant; they are used
48 merely to locate the decimal point. In the example, 2980 g, the zero may also be used to
49 indicate the decimal point, in which case the zero is not significant. Alternately,
50 however, the zero may indicate that the weight is closer to 2981 g or 2979 g, in which
51 case the zero is significant. In such a case, knowledge of the method of measurement
52 would be required in order to indicate whether the zero is or is not significant. In the
53 case of a volume measurement of 298 mL, all of the digits are significant. In a given
54 result, the last significant figure written is approximate but all preceding figures are
55 accurate. For example, a volume of 29.8 mL implies that 8 is approximate. The true
56 volume falls between 29.75 and 29.85. Thus, 29.8 mL is accurate to the nearest 0.1 mL,
57 which means that the measurement has been made within ±0.05 mL. Likewise, a value
58 of 298 mL is accurate to the nearest 1 mL and implies a measurement falling between
59 297.5 and 298.5, which means that the measurement has been made within ±0.5 mL
60 and is subject to a maximum error calculated as follows:
61 (0.5 mL/298 mL) × 100% = 0.17%
62 A zero in a quantity such as 298.0 mL is a significant figure and implies that the
63 measurement has been made within the limits of 297.95 and 298.05 with a possible
64 error calculated as follows:
65 (0.05 mL/298.0 mL) × 100% = 0.017%
66 EXAMPLES—
67

68 1. 29.8 mL = 29.8 ± 0.05 mL (accurate to the nearest 0.1 mL)

69 2. 29.80 mL = 29.80 ± 0.005 mL (accurate to the nearest 0.01 mL)
70 3. 29.800 mL = 29.800 ± 0.0005 mL (accurate to the nearest 0.001 mL)

71 The degree of accuracy in the last example is greatest. Thus, the number of significant
72 figures provides an estimate both of true value and of accuracy.
73 EXAMPLES OF SIGNIFICANT FIGURES—
74

Number of Significant
Measurement Figures
2.98 3
2.980 4
0.0298 3
0.0029 2

75 Calculations—All figures should be retained until the calculations have been

76 completed. Only the appropriate number of significant figures, however, should be
77 retained in the final result.
78 Determining the number of significant figures—
79 Sums and Differences—When adding or subtracting, the number of decimal places in
80 the result shall be the same as the number of decimal places in the component with the
81 fewest decimal places.
82 EXAMPLE—

83 11.5 + 11.65 + 9.90 = 33.1

84 Products and Quotients—When multiplying or dividing, the result shall have no more
85 significant figures than the measurement with the smallest number of significant figures
86 entering into the calculation.
 87 EXAMPLE—

88 4.266 × 21 = 90
89 Rounding Off—For rules on rounding off measurements or calculated results, see
90 Interpretation of Requirements under Significant Figures and Tolerances in the General
91 Notices. Note, however, that in the example above, if 21 is an absolute number (e.g.,
92 the number of doses), then the answer, 89.586, is rounded off to 89.59 which has 4
93 significant figures.
94 LOGARITHMS
95 The logarithm of a number is the exponent or the power to which a given base must be
96 raised in order to equal that number.
97 Definitions—
98 pH = −log [H+], and
99 pKa = −log Ka
100 pH = −log [H+], and pKa = −log Ka, where [H+] is the hydrogen ion concentration in an
101 aqueous solution and Ka is the ionization constant of the acid in an aqueous solution.
102 The [H+] = the antilogarithm of (−pH), and the Ka = the antilogarithm of (−pKa).
103 The pH of an aqueous solution containing a weak acid may be calculated using the
104 Henderson-Hasselbalch equation:
105 pH = pKa + log [salt]/[acid]
106 EXAMPLE—
107 A solution contains 0.020 moles per L of sodium acetate and 0.010 mole per L of
108 acetic acid, which has a pKa value of 4.76. Calculate the pH and the [H+] of the solution.
109 Substituting into the above equation, pH = 4.76 + log (0.020/0.010) = 5.06, and the [H+]
110 = antilogarithm of (−5.06) = 8.69 × 10−6.
111
112 BASIC PHARMACEUTICAL CALCULATIONS
113 The remainder of this chapter will focus on basic pharmaceutical calculations. It is
114 important to recognize the rules involved when adding, subtracting, dividing, and
115 multiplying values. The interrelationships between various units within the different
116 weighing and measuring systems are also important and have to be understood.
117 CALCULATIONS IN COMPOUNDING
118 The pharmacist must be able to calculate the amount or concentration of drug
119 substances in each unit or dosage portion of a compounded preparation at the time it is
120 dispensed. Pharmacists must perform calculations and measurements to obtain,
121 theoretically, 100% of the amount of each ingredient in compounded formulations.
122 Calculations must account for the active ingredient, or active moiety, and water content
123 of drug substances, which includes that in the chemical formulas of hydrates. Official
124 drug substances and added substances must meet the requirements under Loss on
125 Drying 731 , which must be included in the calculations of amounts and
126 concentrations of ingredients. The pharmacist should consider the effect of ambient
127 humidity on the gain or loss of water from drugs and added substances in containers
128 subjected to intermittent opening over prolonged storage. Each container should be
129 opened for the shortest duration necessary and then closed tightly immediately after
130 use.
131 The nature of the drug substance that is to be weighed and used in compounding a
132 prescription must be known exactly. If the substance is a hydrate, its anhydrous
133 equivalent weight may need to be calculated. On the other hand, if there is adsorbed
134 moisture present that is either specified on a certificate of analysis or that is determined
135 in the pharmacy immediately before the drug substance is used by the procedure under
136 Loss on Drying 731 , this information must be used when calculating the amount of
137 drug substance that is to be weighed in order to determine the exact amount of
138 anhydrous drug substance required.
139 There are cases in which the required amount of a dose is specified in terms of a
140 cation [e.g., Li+, netilmicin (n+)], an anion [e.g., F−], or a molecule (e.g., theophylline in
141 aminophylline). In these instances, the drug substance weighed is a salt or complex, a
142 portion of which represents the pharmacologically active moiety. Thus, the exact
143 amount of such substances weighed must be calculated on the basis of the required
144 quantity of the pharmacological moiety.
145 The following formula may be used to calculate the exact theoretical weight of an
146 ingredient in a compounded preparation:
147 W = ab/de
148 in which W is the actual weighed amount; a is the prescribed or pharmacist-determined
149 weight of the active or functional moiety of drug or added substance; b is the chemical
150 formula weight of the ingredient, including waters of hydration for hydrous ingredients; d
151 is the fraction of dry weight when the percent by weight of adsorbed moisture content is
152 known from the loss on drying procedure (see Loss on Drying 731 ); and e is the
153 formula weight of the active or functional moiety of a drug or added substance that is
154 provided in the formula weight of the weighed ingredient.
155 Example 1: Triturate Morphine Sulfate USP and Lactose NF to obtain 10 g in which
156 there are 30 mg of Morphine Sulfate USP for each 200 mg of the morphine-lactose
157 mixture. [NOTE—Clinical dosages of morphine mean Morphine Sulfate USP, which is the
158 pentahydrate.]

Equation Factor Numerical Value

W weight, in g, of Morphine Sulfate USP
a 1.5 g of morphine sulfate pentahydrate in the prescription
b 759 g/mole
d 1.0
e 759 g/mole
159 W = (1.5 g × 759 g/mole)/(1.0 × 759 g/mole) = 1.5 g
160 Example 2: Accurately weigh an amount of Aminophylline USP to obtain 250 mg of
161 anhydrous theophylline. [NOTE—The powdered aminophylline dihydrate weighed
162 contains 0.4% w/w adsorbed moisture as stated in the Certificate of Analysis.]
 Equation Factor Numerical Value
W weight, in mg, of Aminophylline USP (dihydrate)
a 250 mg of theophylline
b 456 g/mole
d 0.996
e 360 g/mole
163 W = (250 mg × 456 g/mole)/(0.996 × 360 g/mole) = 318 mg
164 Example 3: Accurately weigh an amount of Lithium Citrate USP (containing 2.5%
165 moisture as stated in the Certificate of Analysis) to obtain 200 mEq of lithium (Li+).
166 [NOTE—One mEq of Li+ is equivalent to 0.00694 g of Li+.]

Equation Factor Numerical Value

W weight, in g, of Lithium Citrate USP (tetrahydrate)
a 200 mEq of Li+ or 1.39 g of Li+
b 282 g/mole
d 0.975
e 3 × 6.94 g/mole or 20.8 g/mole
167 W = (1.39 g × 282 g/mole)/(0.975 × 20.8 g/mole) = 19.3 g
168 Example 4: Accurately weigh an amount of Netilmicin Sulfate USP, equivalent to 2.5 g
169 of netilmicin. [NOTE—Using the procedure under Loss on Drying 731 , the Netilmicin
170 Sulfate USP that was weighed lost 12% of its weight.]

Equation Factor Numerical Value

W weight, in g, of Netilmicin Sulfate USP
a 2.5 g
b 1442 g/mole
d 0.88
e 951 g/mole
171 W = (2.5 g × 1442 g/mole)/(0.88 × 951 g/mole) = 4.31 g
172 BUFFER SOLUTIONS

173 Definition—A buffer solution is an aqueous solution that resists a change in pH when
174 small quantities of acid or base are added, when diluted with the solvent, or when the
175 temperature changes. Most buffer solutions are mixtures of a weak acid and one of its
176 salts or mixtures of a weak base and one of its salts. Water and solutions of a neutral
177 salt such as sodium chloride have very little ability to resist the change of pH and are
178 not capable of effective buffer action.
179 Preparation, Use, and Storage of Buffer Solutions—Buffer solutions for
180 Pharmacopeial tests should be prepared using freshly boiled and cooled water (see
181 Standard Buffer Solutions under Buffer Solutions in Reagents, Indicators, and
182 Solutions). They should be stored in containers such as Type I glass bottles and used
183 within 3 months of preparation.
184 Buffers used in physiological systems are carefully chosen so as not to interfere with
185 the pharmacological activity of the medicament or the normal function of the organism.
186 Commonly used buffers in parenteral products, for example, are acetic, citric, glutamic,
187 and phosphoric acids and their salts. Buffer solutions should be freshly prepared.
188 The Henderson-Hasselbalch equation, noted above, allows the pH of a buffer solution
189 of a weak acid and its salt to be calculated. Appropriately modified, this equation may
190 be applied to buffer solutions composed of a weak base and its salt.
191 Buffer Capacity—The buffer capacity of a solution is the measurement of the ability of
192 that solution to resist a change in pH upon addition of small quantities of a strong acid
193 or base. An aqueous solution has a buffer capacity of 1 when 1 L of the buffer solution
194 requires 1 gram equivalent of strong acid or base to change the pH by 1 unit. Therefore,
195 the smaller the pH change upon the addition of a specified amount of acid or base, the
196 greater the buffer capacity of the buffer solution. Usually, in analysis, much smaller
197 volumes of buffer are used in order to determine the buffer capacity. An approximate
198 formula for calculating the buffer capacity is gram equivalents of strong acid or base
199 added per L of buffer solution per unit of pH change, i.e., (Eq/L)/(pH change).
200 EXAMPLE—
201 The addition of 0.01 g equivalents of sodium hydroxide to 0.25 L of a buffer solution
202 produced a pH change of 0.50. The buffer capacity of the buffer solution is calculated as
203 follows:
204 (0.01/0.25)/0.50 = 0.08(Eq/L)/(pH change)
205 DOSAGE CALCULATIONS

206 Special Dosage Regimens—Geriatric and pediatric patients require special

207 consideration when designing dosage regimens. In geriatric patients, the organs are
208 often not functioning efficiently as a result of age-related pharmacokinetic changes or
209 disease. For these patients, modifications in dosing regimens are available in
210 references such as USP Drug Information.
211 For pediatric patients, where organs are often not fully developed and functioning,
212 careful consideration must be applied during dosing. Modifications in dosing regimens
213 for pediatric patients are also available in references such as USP Drug Information.
214 General rules for calculating doses for infants and children are available in pharmacy
215 calculation textbooks. These rules are not drug-specific and should be used only in the
216 absence of more complete information.
217 The usual method for calculating a dose for children is to use the information provided
218 for children for the specific drug. The dose is frequently expressed as mg of drug per kg
219 of body weight for a 24-hour period, and is then usually given in divided portions.
220 The calculation may be made using the following equation:
221 (mg of drug per kg of body weight ) × (kg of body weight) = dose for an individual for a
222 24-hour period
223 A less frequently used method of calculating the dose is based on the surface area of
224 the individual's body. The dose is expressed as amount of drug per body surface area in
225 m2, as shown in the equation below:
226 (amount of drug per m2 of body surface area) × (body surface area in m2) = dose for an
227 individual for a 24-hour period
228 The body surface area (BSA) may be determined from nomograms relating height and
229 weight in dosage handbooks. The BSA for adult and pediatric patients may also be
230 determined using the following equations:
231 BSA (m2) = square root of {[Height (in) × Weight (lb)]/3131}
232 or
233 BSA (m2) = square root of {[Height (cm) × Weight (kg)]/ 3600}
234 EXAMPLE—
235 Rx for Spironolactone Suspension 25 mg/tsp. Sig: 9 mg BID for an 18 month-old child
236 who weighs 22 lbs.
237 The USP DI 2002, 22nd ed., states that the normal pediatric dosing regimen for
238 Spironolactone is 1 to 3 mg per kg per day. In this case, the weight of the child is 22 lbs,
239 which equals 22 lbs/(2.2 lbs/kg) = 10 kg. Therefore the normal dose for this child is 10 to
240 30 mg per day and the dose ordered is 18 mg per day as a single dose or divided into 2
241 to 4 doses. The dose is acceptable based on published dosing guidelines.
242 PERCENTAGE CONCENTRATIONS
243 Percentage concentrations of solutions are usually expressed in one of three common
244 forms:
245 Volume percent (v/v) = Volume of solute/Volume of solution × 100%
246 Weight percent (w/w) = (Weight of solute × 100%)/Weight of solution
247 Weight in volume percent (w/v) = (Weight of solute (in g)/Volume of solution (in mL)) ×
248 100%
249 See also Percentage Measurements under Concentrations in the General Notices. The
250 above three equations may be used to calculate any one of the three values (i.e.,
251 weights, volumes, or percentages) in a given equation if the other two values are
252 known.
253 Note that weights are always additive, i.e., 50 g plus 25 g = 75 g. Volumes of two
254 different solvents or volumes of solvent plus a solid solute are not strictly additive. Thus
255 50 mL of water + 50 mL of pure alcohol do not produce a volume of 100 mL.
256 Nevertheless, it is assumed that in some pharmaceutical calculations, volumes are
257 additive, as discussed below under Reconstitution of Drugs Using Volumes Other than
258 Those on the Label.
259 EXAMPLES—
260

261 1. Calculate the percentage concentrations (w/w) of the constituents of the solution
262 prepared by dissolving 2.50 g of phenol in 10.00 g of glycerin. Using the weight
263 percent equation above, the calculation is as follows.
264 Total weight of the solution = 10.00 g + 2.50 g = 12.50 g

265 Weight percent of phenol = (2.50 g × 100%)/12.50 g = 20.0% of phenol

266 Weight percent of glycerin = (10 g × 100%)/12.50 g = 80.0% of glycerin

267 2. A prescription order reads as follows:

268 Eucalyptus Oil 3% (v/v) in Mineral Oil.

269 Dispense 30.0 mL.

270 What quantities should be used for this prescription? Using the volume percent
271 equation above, the calculation is as follows.

272 Amount of Eucalyptus Oil:

273 3% = (Volume of oil in mL/30.0 mL) × 100%

274 Solving the equation, the volume of oil = 0.90 mL.

275 Amount of Mineral Oil: To 0.90 mL of Eucalyptus Oil add sufficient Mineral Oil to
276 prepare 30.0 mL.

277 3. A prescription order reads as follows:

Zinc oxide 7.5 g

Calamine 7.5 g
Starch 15 g
White petrolatum 30 g

278 4. Calculate the percentage concentration for each of the four components. Using
279 the weight percent equation above, the calculation is as follows.
280 5. Total weight = 7.5 g + 7.5 g + 15 g + 30 g = 60.0 g
281 6. Weight percent of zinc oxide = (7.5 g zinc oxide/60 g ointment) × 100% = 12.5%
282 7. Weight percent of calamine = (7.5 g calamine/60 g ointment) × 100% = 12.5%
283 8. Weight percent of starch = (15 g starch/60 g ointment) × 100% = 25%
284 9. Weight percent of white petrolatum = (30 g white petrolatum/60 g ointment) ×
285 100% = 50%

286 SPECIFIC GRAVITY

287 The definition of specific gravity is usually based on the ratio of weight of a substance
288 in air at 25° to that of the weight of an equal volume of water at the same temperature.
289 The weight of 1 mL of water at 25° is approximately 1 g. The following equation may be
290 used for calculations.
291 Specific Gravity = (Weight of the substance)/(Weight of an equal volume of water)
292 EXAMPLES—
293

294 1. A liquid weighs 125 g and has a volume of 110 mL. What is the specific gravity?

295 The weight of an equal volume of water is 110 g.

296 Using the above equation,

297 specific gravity = 125 g/110 g = 1.14

298 2. Hydrochloric Acid NF is approximately a 37% (w/w) solution of hydrochloric acid

299 (HCl) in water. How many grams of HCl are contained in 75.0 mL of HCl NF?
300 (Specific gravity of Hydrochloric Acid NF is 1.18.)

301 Calculate the weight of HCl NF using the above equation.

302 The weight of an equal volume of water is 75 g.

303 Specific Gravity 1.18 = weight of the HCl NF g/75.0 g

304 Solving the equation, the weight of HCl NF is 88.5 g.

305 Now calculate the weight of HCl using the weight percent equation.

306 37.0 % (w/w) = (weight of solute g/88.5 g ) × 100

307 Solving the equation, the weight of the HCl is 32.7 g.

308 DILUTION AND CONCENTRATION

309 A concentrated solution can be diluted. Powders and other solid mixtures can be
310 triturated or diluted to yield less concentrated forms. Because the amount of solute in
311 the diluted solution or mixture is the same as the amount in the concentrated solution or
312 mixture, the following relationship applies to dilution problems.
313 The quantity of Solution 1 (Q1) × concentration of Solution 1 (C1) = the quantity of
314 Solution 2 (Q2) × concentration of Solution 2 (C2), or
315 (Q1)(C1) = (Q2)(C2)
316 Almost any quantity and concentration terms may be used. However, the units of the
317 terms must be the same on both sides of the equation.
318 EXAMPLES—
319 1. Calculate the quantity (Q2), in g, of diluent that must be added to 60 g of a 10%
320 (w/w) ointment to make a 5% (w/w) ointment. Let

321 (Q1) = 60 g, (C1) = 10%, and (C2) = 5%

322 Using the above equation,

323 60 g × 10% = (Q2) × 5% (w/w)

324 Solving the above equation, the quantity of product needed, Q2, is 120 g. The
325 initial quantity of product added was 60 g, and therefore an additional 60 g of
326 diluent must be added to the initial quantity to give a total of 120 g.

327 2. How much diluent should be added to 10 g of a trituration (1 in 100) to make a
328 mixture that contains 1 mg of drug in each 10 g of final mixture?

329 Determine the final concentration by first converting mg to g. One mg of drug in

330 10 g of mixture is the same as 0.001g in 10 g. Let

331 (Q1) = 10 g, (C1) = (1 in 100),

332 and

333 (C2) = (0.001 in 10)

334 Using the equation for dilution,

335 10 g × (1/100) = (Q2) g × (0.001/10)

336 Solving the above equation,

337 (Q2) = 1000 g

338 Because 10 g of the final mixture contains all of the drug and some diluent,
339 (1000 g − 10 g) or 990 g of diluent is required to prepare the mixture at a
340 concentration of 0.001 g of drug in 10 g of final mixture.

341 3. Calculate the percentage strength of a solution obtained by diluting 400 mL of a

342 5.0% solution to 800 mL. Let

343 (Q1) = 400 mL, (C1) = 5%, and (Q2) = 800 mL

344 Using the equation for dilution,

345 400 mL × 5% = 800 mL × (C2)%

346 Solving the above equation,

347 (C2) = 2.5% (w/v)

348 USE OF POTENCY UNITS

349 See Units of Potency in the General Notices.
350 Because some substances may not be able to be defined by chemical and physical
351 means, it may be necessary to express quantities of activity in biological units of
352 potency.
353 EXAMPLES—

354 1. One mg of Pancreatin contains not less than 25 USP Units of amylase activity,
355 2.0 USP Units of lipase activity, and 25 USP Units of protease activity. If the
356 patient takes 0.1 g (100 mg) per day, what is the daily amylase activity
357 ingested?

358 1 mg of Pancreatin corresponds to 25 USP Units of amylase activity.

359 100 mg of Pancreatin corresponds to

360 100 × (25 USP Units of amylase activity) = 2500 Units

361 2. A dose of penicillin G benzathine for streptococcal infection is 1.2 million units
362 intramuscularly. If a specific product contains 1180 units per mg, how many
363 milligrams would be in the dose?

364 1180 units of penicillin G benzathine are contained in 1 mg.

365 1 unit is contained in 1/1180 mg.

366 1,200,000 units are contained in

367 (1,200,000 × 1)/1180 units = 1017 mg

368 BASE VS SALT OR ESTER FORMS OF DRUGS

369 Frequently, for stability or other reasons such as taste or solubility, the base form of a
370 drug is administered in an altered form such as an ester or salt. This altered form of the
371 drug usually has a different molecular weight (MW), and at times it may be useful to
372 determine the amount of the base form of the drug in the altered form.
373 EXAMPLES—

374 1. Four hundred milligrams of erythromycin ethylsuccinate (molecular weight,

375 862.1) is administered. Determine the amount of erythromycin (molecular
376 weight, 733.9) in this dose.

377 862.1 g of erythromycin ethylsuccinate corresponds to 733.9 g of erythromycin.

378 1 g of erythromycin ethylsuccinate corresponds to (733.9/862.1) g of
379 erythromycin.

380 0.400 g of erythromycin ethylsuccinate corresponds to (733.9/862.1) × 0.400 g

381 or 0.3405 g of erythromycin.

382 2. The molecular weight of testosterone cypionate is 412.6 and that of testosterone
383 is 288.4. What is the dose of testosterone cypionate that would be equivalent to
384 60.0 mg of testosterone?

385 288.4 g of testosterone corresponds to 412.6 g of testosterone cypionate.

386 1 g of testosterone corresponds to 412.6/288.4 g of testosterone cypionate.

387 60.0 mg or 0.0600 g of testosterone corresponds to (412.6/288.4) × 0.0600 =

388 0.0858 g or 85.8 mg of testosterone cypionate.

389 RECONSTITUTION OF DRUGS USING VOLUMES OTHER THAN THOSE ON THE LABEL
390 Occasionally it may be necessary to reconstitute a powder in order to provide a
391 suitable drug concentration in the final product. This may be accomplished by
392 estimating the volume of the powder and liquid medium required.
393 EXAMPLES—

394 1. If the volume of 250 mg of ceftriaxone sodium is 0.1 mL, how much diluent
395 should be added to 500 mg of ceftriaxone sodium powder to make a
396 suspension having a concentration of 250 mg per mL?

397 500 mg × (1 mL/250 mg) = 2 mL

398 Volume of 500 mg of ceftriaxone sodium = 500 mg × (0.1 mL/250 mg) = 0.2 mL

399 Volume of the diluent required = (2 mL of suspension) − (0.2 mL of Ceftriaxone

400 Sodium) = 1.8 mL

401 2. What is the volume of dry powder cefonicid, if 2.50 mL of diluent is added to 1 g
402 of powder to make a solution having a concentration of 325 mg per mL?

403 Volume of solution containing 1 g of the powder = 1 g of cefonicid × (1000
404 mg/1 g) × (1 mL of solution/325 mg of cefonicid) = 3.08 mL

405 Volume of dry powder cefonicid = 3.08 mL of solution − 2.50 mL of diluent =

406 0.58 mL.

407 ALLIGATION ALTERNATE AND ALGEBRA

408 Alligation—Alligation is a rapid method of determining the proportions in which

409 substances of different strengths are mixed to yield a desired strength or concentration.
410 Once the proportion is found, the calculation may be performed to find the exact
411 amounts of substances required. Set up the problem as follows.

412 1. Place the desired percentage or concentration in the center.

413 2. Place the percentage of the substance with the lower strength on the lower left-
414 hand side.
415 3. Place the percentage of the substance with the higher strength on the upper left-
416 hand side.
417 4. Subtract the desired percentage from the lower percentage, and place the
418 obtained difference on the upper right-hand side.
419 5. Subtract the higher percentage from the desired percentage, and place the
420 obtained difference on the lower right-hand side.

421 The results obtained will determine how many parts of the two different percentage
422 strengths should be mixed to produce the desired percentage strength of a drug
423 mixture.
424 EXAMPLES—

425 1. How much ointment having a 12% drug concentration and how much ointment
426 having a 16% drug concentration must be used to make 1 kg of a preparation
427 containing a 12.5% drug concentration?

428

429 In a total of 4.0 parts of 12.5% product, 3.5 parts of 12% ointment and 0.5 parts
430 of 16% ointment are needed.

431 4 parts correspond to 1 kg or 1000 g.

432 1 part corresponds to 250 g.

433 3.5 parts correspond to 3.5 × 250 g or 875 g.

434 0.5 parts correspond to 0.5 × 250 g or 125 g.

435 2. How many mL of 20% dextrose in water and 50% dextrose in water are needed
436 to make 750 mL of 35% dextrose in water?

437

438 In a total of 30 parts of 35% dextrose in water, 15 parts of 50% dextrose in

439 water and 15 parts of 20% dextrose in water are required.

440 30 parts correspond to 750 mL.

441 15 parts correspond to 375 mL.

442 Thus use 375 mL of the 20% solution and 375 mL of the 50% solution to
443 prepare the product.

444 Algebra—Instead of using alligation to solve the above problems, algebra may be used,
445 following the scheme outlined below.
446 In order to represent the total quantity (weights, parts, or volumes) of the final mixture
447 or solution, 1 or a specified quantity is used.
448 Let x be the quantity of one portion and [1 (or the specified amount) − x] be the
449 remaining portion. Set up the equation according to the statement below, and solve.
450 The amount of drug in one part plus the amount of drug in the other part equals the
451 total amount in the final mixture or solution.
452 EXAMPLES—

453 1. How much ointment having a 12% drug concentration and how much ointment
454 having a 16% drug concentration must be used to make 1 kg of a preparation
455 containing a 12.5% drug concentration?

456 Let 1 kg be the total quantity of ointment to be prepared, let x be the quantity, in
457 kg, of the 12% ointment, and let (1 − x) be the quantity in kg of the 16%
458 ointment. The equation is as follows:

459 (12/100) x + (16/100)(1 − x) = (12.5/100)(1)

460 Solving the equation, x equals 0.875 kg of the 12% ointment and (1 − x) equals
461 (1 − 0.875) or 0.125 kg of the 16% ointment.

462 2. How many mL of 20% dextrose in water and 50% dextrose in water are needed
463 to make 750 mL of 35% dextrose in water?

464 Let x be the volume, in mL, of the 20% solution, and let (750 − x) be the volume
465 in mL of the 50% solution. The equation is as follows:

466 (20/100)x + (50/100)(750 − x) = (35/100)(750)

467 Solving the equation, x equals 375 mL of the 20% solution and (750 − x) equals
468 (750 − 375) or 375 mL of the 50% solution.

469 MOLAR, MOLAL, AND NORMAL CONCENTRATIONS

470 See Concentrations in the General Notices.
471 Molarity—The molar concentration, M, of the solution is the number of moles of the
472 solute contained in one L of solution.
473 Molality—The molal concentration, m, is the number of moles of the solute contained in
474 one kilogram of solvent.
475 Normality—The normal concentration, N, of a solution expresses the number of
476 milliequivalents (mEq) of solute contained in 1 mL of solution or the number of
477 equivalents (Eq, gram-equivalent weight) of solute contained in 1 L of solution. When
478 using normality, the pharmacist must apply quantitative chemical analysis principles
479 using molecular weight (MW). Normality depends on the reaction capacity of a chemical
480 compound and therefore the reaction capacity must be known. For acids and bases,
481 reaction capacity is the number of accessible protons available from, or the number of
482 proton binding sites available on, each molecular aggregate. For electron transfer
483 reactions, reaction capacity is the number of electrons gained or lost per molecular
484 aggregate.
485 EXAMPLES—

486 1. How much sodium bicarbonate powder is needed to prepare 50.0 mL of a 0.07 N
487 solution of sodium bicarbonate (NaHCO3)? (MW of NaHCO3 is 84.0 g per mol.)

488 In an acid or base reaction, because NaHCO3 may act as an acid by giving up
489 one proton, or as a base by accepting one proton, one Eq of NaHCO3 is
490 contained in each mole of NaHCO3. Thus the equivalent weight of NaHCO3 is
491 84 g. [NOTE—The volume, in L, × normality of a solution equals the number of
492 equivalents in the solution.]

493 The number of equivalents of NaHCO3 required = (0.07 Eq/L)(50.0 mL/1000 mL

494 /L) = 0.0035 equivalents.

495 1 equivalent weight is 84.0 g.

496 0.0035 equivalents equals 84.0 g/Eq × 0.0035 Eq = 0.294 g.

497 2. A prescription calls for 250 mL of a 0.1 N hydrochloric acid (HCl) solution. How
498 many mL of concentrated hydrochloric acid are needed to make this solution?
499 [NOTE—The specific gravity of concentrated hydrochloric acid is 1.18, the
500 molecular weight is 36.46 and the concentration is 37.5% (w/w). Because
501 hydrochloric acid functions as an acid and reacts by giving up one proton in a
502 chemical reaction, 1 Eq is contained in each mole of the compound. Thus the
503 equivalent weight is 36.46 g.]

504 The number of equivalents of HCl required is 0.250 L × 0.1 N = 0.025

505 equivalents.

506 1 equivalent is 36.46 g.

507 0.025 equivalents correspond to 0.025 Eq × 36.46 g/Eq = 0.9115 g.

508 37.5 g of pure HCl are contained in 100 g of concentrated HCl.

509 Thus 1 g of pure HCl is contained in (100/37.5) g = 2.666 g of concentrated

510 acid, and 0.9115 g is contained in (0.9115 × 2.666) g or 2.43 g of concentrated
511 acid.

512 In order to determine the volume of the supplied acid required, use the
513 definition for specific gravity as shown below.

514 Specific gravity = (weight of the substance)/(weight of an equal volume of

515 water).

516 1.18 = 2.43 g/(weight of an equal volume of water).

517 The weight of an equal volume of water is 2.056 g or 2.06 g, which measures
518 2.06 mL. Thus, 2.06 mL of concentrated acid is required.

519 MILLIEQUIVALENTS AND MILLIMOLES

520 NOTE—This section addresses milliequivalents (mEq) and millimoles (mmol) as they
521 apply to electrolytes for dosage calculations.
522 The quantities of electrolytes administered to patients are usually expressed in terms
523 of mEq. This term must not be confused with a similar term used in quantitative
524 chemical analysis as discussed above. Weight units such as mg or g are not often used
525 for electrolytes because the electrical properties of ions are best expressed as mEq. An
526 equivalent is the weight of a substance (equivalent weight) that supplies one unit of
527 charge. An equivalent weight is the weight, in g, of an atom or radical divided by the
528 valence of the atom or radical. A milliequivalent is one-thousandth of an equivalent (Eq).
529 Because the ionization of phosphate depends on several factors, the concentration is
530 usually expressed in millimoles, moles, or milliosmoles, which are described below.
531 [NOTE—Equivalent weight (Eq.wt) = wt. of an atom or radical (ion) in g/valence (or
532 charge) of the atom or radical. Milliequivalent weight (mEq.wt) = Eq.wt. (g)/1000.]
533 EXAMPLES—

534 1. Potassium (K+) has a gram-atomic weight of 39.10. The valence of K+ is 1+.
535 Calculate its milliequivalent weight (mEq wt).

536 Eq wt = 39.10 g/1 = 39.10 g

537 mEq wt = 39.10 g/1000 = 0.03910 g = 39.10 mg

538 2. Calcium (Ca2+) has a gram-atomic weight of 40.08. Calculate its milliequivalent
539 weight (mEq wt).

540 Eq wt = 40.08 g/2 = 20.04 g

541 mEq wt. = 20.04 g/1000 = 0.02004 g = 20.04 mg

542 NOTE—The equivalent weight of a compound may be determined by dividing the

543 molecular weight in g by the product of the valence of either relevant ion and
544 the number of times this ion occurs in one molecule of the compound.

545 3. How many milliequivalents of potassium ion (K+) are there in a 250-mg Penicillin
546 V Potassium Tablet? [NOTE—Molecular weight of penicillin V potassium is
547 388.48 g per mol; there is one potassium atom in the molecule; and the valence
548 of K+ is 1.]

549 Eq wt = 388.48 g/[1(valence) × 1 (number of charges)] = 388.48 g

550 mEq wt = 388.48 g/1000 = 0.38848 g = 388.48 mg

551 (250 mg per Tablet)/(388.48 mg per mEq) = 0.644 mEq of K+ per Tablet

552 4. How many equivalents of magnesium ion and sulfate ion are contained in 2 mL
553 of a 50% Magnesium Sulfate Injection? (Molecular weight of MgSO4 · 7H2O is
554 246.48 g per mol.)

555 Amount of magnesium sulfate in 2 mL of 50% Magnesium Sulfate Injection

556 2 mL of Injection × (50 g of magnesium sulfate/100 mL of Injection) = 1 g

557 Eq wt of MgSO4 · 7H2O = MW (g)/(valence of specified ion × number of specified

558 ions in one mole of salt).

559 For the magnesium ion:

560 The number of equivalents is calculated as follows:

561 246.48/[2(valence) × 1 (number of ions in the compound)] = 123.24 g/Eq of

562 magnesium ion

563 The number of equivalents in 1 g is 1g/123.24 g/Eq = 0.008114 Eq.

564 The number of mEq may be calculated as follows:

565 The mEq wt = Eq wt (g)/1000 = (123.24 g/Eq)/1000 = 0.12324 g

566 The number of milliequivalents of magnesium ion in 1 g is

567 1g/0.12324 g/mEq = 8.114 mEq

568 For the sulfate ion:

569 The number of equivalents is calculated as follows:

570 246.48/[2(valence) × 1 (number of ions in the compound)] = 123.24 g/Eq of

571 sulfate ion

572 The number of equivalents in 1 g is

573 1g/123.24 g/Eq = 0.008114 Eq

574 The number of mEq may be calculated as follows:

575 The mEq wt = Eq wt (g)/1000 = (123.24 g/Eq)/1000 = 0.12324 g

576 The number of milliequivalents of sulfate ion in 1 g is

577 1g/0.12324 g/mEq = 8.114 mEq

578 5. A vial of Sodium Chloride Injection contains 3 mEq of sodium chloride per mL.
579 What is the percentage strength of this solution? (Molecular weight of sodium
580 chloride is 58.44 g per mol.)

581 1 mEq = 1 Eq/1000 = 58.44 g/1000 = 0.05844 g = 58.44 mg

582 Amount of sodium chloride in 3 mEq per mL = 58.44 mg per mEq × 3 mEq per
583 mL = 175.32 mg per mL.

584 175.32 mg/1 mL = 17532 mg/100 mL = 17.532 g/100 mL = 17.5%

585 Using mols and mmols—

586 A number of countries have adopted the International System of Units and no longer
587 calculate doses using mEq as described above, but instead use the terms moles (mol)
588 and millimoles (mmol). In USP–NF or in the Pharmacists' Pharmacopeia the
589 International System of Units is used except for the labeling of electrolytes.
590 Definitions—
591 A mole equals one gram atomic weight or gram molecular weight of a substance.
592 A millimole equals 1/1000 of a mole.
593 EXAMPLES—

594 1. Potassium (K) has a gram-atomic weight of 39.10. Calculate its weight in
595 millimoles (mmol).

596 The weight of one mole is 39.10 g and the weight in millimoles is

597 39.10 g/1000 = 0.0391 g or 39.1 mg

598 2. How many millimoles of Penicillin V are in a tablet that contains 250 mg of
599 Penicillin V Potassium? (Molecular weight of penicillin V potassium is 388.48 g
600 per mol.)

601 The weight of one mole is 388.48 and the weight in millimoles is

602 388.48/1000 = 0.3848 g or 388.48 mg

603 Thus there are 250 mg/388.48 mg/mmol = 0.644 mmol of Penicillin V ion per
604 tablet.

605 ISOOSMOTIC SOLUTIONS

606 The following discussion and calculations have therapeutic implications in preparations
607 of dosage forms intended for ophthalmic, subcutaneous, intravenous, intrathecal, and
608 neonatal use.
609 Cells of the body, such as erythrocytes, will neither swell nor shrink when placed in a
610 solution that is isotonic with the body fluids. However, the measurement of tonicity, a
611 physiological property, is somewhat difficult. It is found that a 0.9% (w/v) solution of
612 sodium chloride, which has a freezing point of −0.52°, is isotonic with body fluids and is
613 said to be isoosmotic with body fluids. In contrast to isotonicity, the freezing point
614 depression is a physical property. Thus many solutions that are isoosmotic with body
615 fluids are not necessarily isotonic with body fluids, e.g., a solution of urea. Nevertheless
616 many pharmaceutical products are prepared using freezing point data or related sodium
617 chloride data to prepare solutions that are isoosmotic with the body fluids. A closely
618 related topic is osmolarity (see Osmolality and Osmolarity 785 ).
619 Freezing point data or sodium chloride equivalents of pharmaceuticals and excipients
620 (see Table 1 below) may be used to prepare isoosmotic solutions, as shown in the
621 examples below.
622 Table 1. Sodium Chloride Equivalents (E) and Freezing Point (FP) Depressions for
623 a 1% Solution of the Drug or Excipient

Drug or Excipient E FP Depression

Atropine sulfate 0.13 0.075
Sodium chloride 1.00 0.576
624 EXAMPLE—
625 Determine the amount of sodium chloride required to prepare 60 mL of an isoosmotic
626 solution of atropine sulfate 0.5% using the sodium chloride equivalent values and also
627 the freezing point depression values.
628 Using the sodium chloride equivalent values—
629 The total amount of substances equivalent to sodium chloride (for a 0.9% solution) =
630 (0.9 g/100 mL) × 60 mL = 0.54 g.
631 The amount of atropine sulfate required = (0.5 g/100 mL) × 60 mL = 0.3 g.
632 1 g of atropine sulfate is equivalent to 0.13 g of sodium chloride.
633 0.3 g atropine sulfate is equivalent to 0.3 × 0.13 g = 0.039 g of sodium chloride.
634 Thus the required amount of sodium chloride is 0.54 − 0.039 = 0.501 g or 0.50 g.
635 Using freezing point depression values—
636 The freezing point depression required is 0.52°.
637 A 1% solution of atropine sulfate causes a freezing point depression of 0.075°.
638 A 0.5% solution of atropine sulfate causes a freezing point depression of
639 0.075° × 0.5 = 0.0375°
640 The additional freezing point depression required is
641 0.52° − 0.0375° = 0.482°
642 A 1% solution of sodium chloride causes a freezing point depression of 0.576°.
643 A (1%/ 0.576) solution of sodium chloride causes a freezing point depression of 1°.
644 A (1%/ 0.576) × 0.482 = 0.836% solution of sodium chloride causes a freezing point
645 depression of 0.482°.
646 The required amount of sodium chloride is
647 (0.836 g/100 mL) × 60 mL = 0.502 g or 0.50 g
648 FLOW RATES IN INTRAVENOUS SETS
649 Some calculations concerning flow rates in intravenous sets are provided below.
650 [NOTE—Examples below are not to be used for treatment purposes.]
651 EXAMPLES—

652 1. Sodium Heparin 8,000 units in 250 mL Sodium Chloride Injection 0.9% solution
653 are to be infused over 4 hours. The administration set delivers 20 drops per mL.

654 What is the flow rate in mL per hour?

655 In 4 hours, 250 mL are to be delivered.

656 In 1 hour, 250 mL/4 = 62.5 mL are delivered.

657 What is the flow rate in drops per minute?

658 In 60 minutes, 62.5 mL are delivered.

659 In 1 minute, 62.5 mL/60 = 1.04 mL are delivered.

660 1 mL = 20 drops.

661 1.04 mL = 1.04 × 20 drops = 20.8 drops.

662 Thus in 1 minute, 20.8 or 21 drops are administered.

663 2. A 14.5 kg patient is to receive 50 mg of Sodium Nitroprusside in 250 mL of

664 dextrose 5% in water (D5W) at the rate of 1.3 µg per kg per minute. The set
665 delivers 50 drops per mL.

666 Calculate the flow rate in mL per hour.

667 The dose for 1 kg is 1.3 µg per minute.

668 The 14.5 kg patient should receive 14.5 × 1.3 µg = 18.85 µg per minute.

669 50 mg or 50,000 µg of drug are contained in 250 mL of D5W.

670 18.85 µg are contained in 250 mL × 18.85/50,000 = 0.09425 mL D5W, which is

671 administered every minute.

672 In 1 minute, 0.09425 mL are administered.

673 In 1 hour or 60 minutes, 60 × 0.09425 mL = 5.655 or 5.7 mL are administered.

674 Calculate the flow rate in drops per minute.

675 1 mL corresponds to 50 drops per minute.

676 0.09425 mL corresponds to 0.09425 × 50 = 4.712 or 4.7 drops per minute.

677 TEMPERATURE
678 The relationship between Celsius degrees (°C) and Fahrenheit degrees (°F) is
679 expressed by the following equation:
680 9 (°C) = 5 (°F) − 160
681 in which °C and °F are the numbers of Celsius degrees and Fahrenheit degrees,
682 respectively.
683 EXAMPLES—

684 1. Convert 77 °F to Celsius degrees.

685 9(°C) = 5(°F) − 160

686 °C = [5(°F) − 160]/9 = [(5 × 77) − 160]/9 = 25 °C

687 2. Convert 30 °C to Fahrenheit degrees.

688 9(°C) = 5(°F) − 160

689 °F = [9(°C) + 160]/5 = [(9 × 30) + 160]/5 = 86 °F

690 The relationship between the Kelvin and the Celsius scales is expressed by the
691 equation:
692 K = °C + 273.1
693 in which K and °C are the numbers of Kelvin degrees and Celsius degrees, respectively.
694 APPLICATION OF MEAN KINETIC TEMPERATURE
695 See Good Storage and Distribution Practices for Drug Products 1079 for the
696 definition of mean kinetic temperature (MKT). MKT is usually higher than the arithmetic
697 mean temperature and is derived from the Arrhenius equation. MKT addresses
698 temperature fluctuations during the storage period of the product. The mean kinetic
699 temperature, TK, is calculated by the following equation:

700
701 in which ∆H is the heat of activation, which equals 83.144 kJ per mol (unless more
702 accurate information is available from experimental studies); R is the universal gas
703 constant, which equals 8.3144 × 10−3 kJ per degree per mol; T1 is the average
704 temperature, in degrees Kelvin, during the first time period, e.g., the first week; T2 is the
705 average temperature, in degrees Kelvin, during the second time period, e.g., second
706 week; and Tn is the average temperature, in degrees Kelvin during the nth time period,
707 e.g., nth week, n being the total number of temperatures recorded. The mean kinetic
708 temperature is calculated from average storage temperatures recorded over a one-year
709 period, with a minimum of twelve equally spaced average storage temperature
710 observations being recorded (see Good Storage and Distribution Practices for Drug
711 Products 1079 ). This calculation can be performed manually with a pocket calculator
712 or electronically with computer software.
713 EXAMPLES—

714 1. The means of the highest and lowest temperatures for 52 weeks are 25 °C each.
715 Calculate the MKT.
716 n = 52

717 ∆H/R = 10,000 K

718 T1, T2, ...,Tn = 25 °C = 273.1 + 25 = 298.1 K

719 R = 0.0083144 kJ K−1mol−1

720 ∆H = 83.144 kJ per mol

721

722 = −10,000K/(ln[(52 × e−∆H/R × 298.1)/52)]

723 = −10,000K/(ln[(52 × e−33.5458)/52)]

724 −10,000K/−33.5458 = 298.1K = 25.0°C

725 The calculated MKT is 25.0 °C. Therefore the controlled room temperature
726 requirement is met by this pharmacy. [NOTE—If the averages of the highest and
727 lowest weekly temperatures differed from each other and were in the allowed
728 range of 15 °C to 30 °C (see 659 Packaging and Storage Requirements),
729 then each average would be substituted individually into the equation. The
730 remaining two examples illustrate such calculations, except that the monthly
731 averages are used.]

732 2. A pharmacy recorded a yearly MKT on a monthly basis, starting in January and
733 ending in December. Each month, the pharmacy recorded the monthly highest
734 temperature and the monthly lowest temperature, and the average of the two
735 was calculated and recorded for the MKT calculation at the end of the year (see
736 Table 2). From these data the MKT may be estimated or it may be calculated. If
737 more than half of the observed temperatures are lower than 25 °C and a mean
738 lower than 23 °C is obtained, the MKT may be estimated without performing the
739 actual calculation.

740 Table 2. Data for Calculation of MKT

Lowest Highest Average Average

Temperature Temperature Temperature Temperature
n Month (in °C) (in °C) (in °C) (in K) ∆H/RT e−∆H/RT
 Lowest Highest Average Average
Temperature Temperature Temperature Temperature
n Month (in °C) (in °C) (in °C) (in K) ∆H/RT e−∆H/RT
1 Jan. 15 27 21 294.1 34.002 1.710
× 10−15
2 Feb. 20 25 22.5 295.6 33.830 2.033
× 10−15
3 Mar. 17 25 21 294.1 34.002 1.710
× 10−15
4 Apr. 20 25 22.5 295.6 33.830 2.033
× 10−15
5 May 22 27 24.5 297.6 33.602 2.551
× 10−15
6 June 15 25 20 293.1 34.118 1.523
× 10−15
7 July 20 26 23 296.1 33.772 2.152
× 10−15
8 Aug. 22 26 24 297.1 33.659 2.411
× 10−15
9 Sept. 23 27 25 298.1 33.546 2.699
× 10−15
10 Oct. 20 28 24 297.1 33.659 2.411
× 10−15
11 Nov. 20 24 22 295.1 33.887 1.919
× 10−15
12 Dec. 22 28 25 298.1 33.546 2.699
× 10−15

741 a. To estimate the MKT, the recorded temperatures are evaluated and the
742 average is calculated. In this case, the calculated arithmetic mean is
743 22.9 °C. Therefore, the above requirements are met and it can be
744 concluded that the mean kinetic temperature is lower than 25 °C.
745 Therefore, the controlled room temperature requirement is met.
746 b. The second approach is to perform the actual calculation.

747 n = 12
748

749

750 = −10,000K/ln[(2.585 × 10−14)/12]

751 −10,000K/−33.771 = 296.11K = 23.0°C

752 The calculated MKT is 23.0 °C, so the controlled room temperature requirement
753 is met. [NOTE—These data and calculations are used only as an example.]

754 3. An article was stored for one year in a pharmacy where the observed monthly
755 average of the highest and lowest temperatures was 25 °C (298.1 K), except for
756 one month with an average of 28 °C (301.1 K). Calculate the MKT of the
757 pharmacy.

758 n = 12

759

760

761 = −10,000K/(ln[(11 × e−33.546 + 1 × e−33.212)/12])

762 = −10,000K/(ln[(2.9692 × 10−14 + 3.7705 ×10−15)/12])

763 = −10,000K/(ln[(3.3463 × 10−14)/12])

764 = −10,000K/[ln(2.7886 × 10−15)]

765 = −10,000K/−33.513 = 298.39K = 25.29°C

766 The controlled room temperature requirement is not met because the calculated
767 MKT exceeds 25 °C. (See Note in Example 2 above.)

768 4. Using the same calculation technique for controlled room temperature, the MKT
769 for controlled cold temperatures can also be calculated.

770 a. For example, if the mean of the highest and lowest temperatures for
771 each week over a period of 52 weeks was 8 °C (i.e., the same mean for
772 each week), then the MKT can be calculated as follows:

773 TK = −10,000/[ln(52e−∆H/(R × 281.1))/52]

774 TK = −10,000/[ln(e−∆H/(R × 281.1))]

775 TK = −10,000/[ln(e−35.575)]

776 = −10,000/[ln(3.548 × 10−16)]

777 = −10,000/−35.575

778 Tk = 281.1K

779 C = 281.1 − 273.1

780 C = 8°

781 b. In another example, where a variety of average temperatures are used,

782 as would be the case in reality, if the average of the highest and lowest
783 temperatures ranges from 0° to 15 °C, then these averages would be
784 individually substituted into the equation. For simplification of the
785 mathematical process, 10 intervals are shown in Table 3 below. This
786 illustration is intended for calculation of MKT at storage or in transit; i.e.,
787 during shipping or distribution of the critical drug product. These
788 calculations can be performed manually or with a computer.

789 Table 3. Sample Data for MKT Calculations

Low High Average Average

Temperature Temperature Temperature Temperature
Intervals (in °C) (in °C) (in °C) (in K) ∆H/RT e−∆H/RT × 1016
 Low High Average Average
Temperature Temperature Temperature Temperature
Intervals (in °C) (in °C) (in °C) (in K) ∆H/RT e−∆H/RT × 1016
1 0 5 2.5 275.6 36.284 1.746
2 2 8 5 278.1 35.958 2.419
3 3 9 6 279.1 35.829 2.752
4 3 14 8.5 281.6 35.511 3.782
5 7 15 11 284.0 35.211 5.106
6 1 6 3.5 276.6 36.153 1.990
7 5 15 10 283.1 35.323 4.565
8 2 14 8 281.1 35.575 3.548
9 2 6 4 277.1 36.088 2.124
10 3 10 6.5 279.6 35.765 2.934

790 ▪Table of Contents

791 1. INTRODUCTION
792 2. CALCULATING AMOUNTS OF ACTIVE INGREDIENTS
793 3. DOSAGE CALCULATIONS
794 4. USE OF POTENCY UNITS
795 5. VOLUME AND WEIGHT SUMS
796 6. DENSITY AND SPECIFIC GRAVITY
797 7. MILLIEQUIVALENTS AND MILLIMOLES
798 8. CONCENTRATION EXPRESSIONS (with Table 1)
799 9. ALCOHOL
800 10. ALLIGATION ALTERNATE AND ALGEBRA
801 11. ALIQUOT CALCULATIONS
802 12. POWDER VOLUME CALCULATIONS
803 13. INTRAVENOUS FLOW OR INFUSION RATES
804 14. ISOOSMOTIC SOLUTIONS
805 15. pH AND BUFFER CALCULATIONS
806 16. TEMPERATURE
807 17. ENDOTOXINS
808 18. STABILITY AND EXPIRATION DATE CALCULATIONS
809 19. APPENDIX 1: LOGARITHMS (with Table 9 and Table 10)

810
811 1. INTRODUCTION
812 The purpose of this general chapter is to provide general information to assist
813 pharmacists and support personnel in performing the necessary calculations for
814 compounding and dispensing medications. This general chapter is not inclusive of all
815 the information necessary for performing pharmaceutical calculations. For additional
816 information regarding pharmaceutical calculations, consult a pharmaceutical
817 calculations textbook. For additional information on pharmaceutical compounding and
818 drug stability, see: Pharmaceutical Compounding—Nonsterile Preparations 795 ,
819 Pharmaceutical Compounding—Sterile Preparations 797 , and Packaging and
820 Storage Requirements 659 ; Quality Assurance in Pharmaceutical Compounding
821 1163 and Stability Considerations in Dispensing Practice 1191 .
822 Correct pharmaceutical calculations can be accomplished by using proper conversions
823 from one measurement system to another and properly placing decimal points (or
824 commas, in countries where it is customary to use these in the place of decimal points),
825 by understanding the arithmetical concepts, and by paying close attention to the details
826 of the calculations. Before proceeding with any calculation, pharmacists should do the
827 following: (a) read the entire formula or prescription carefully; (b) determine the
828 materials that are needed; and then (c) select the appropriate methods of preparation
829 and the appropriate calculations.
830 Logical methods that require as few steps as possible should be selected to ensure
831 that calculations are done accurately and correctly. A pharmacist should double-check
832 each calculation or have someone else double-check, e.g., a technician, if another
833 pharmacist is not available, before proceeding with compounding the preparation. One
834 expedient method of double-checking is estimation, which consists of convenient
835 rounding (e.g., 0.012 to 0.01, 0.44 to 0.5, 18.3 to 20, and 476 to 500) to approximate the
836 magnitude of answers.
837
838 2. CALCULATING AMOUNTS OF ACTIVE INGREDIENTS
839 The pharmacist must be able to calculate the amount or concentration of drug
840 substances in each unit or dosage portion of a compounded preparation at the time it is
841 prepared and again at the time it is dispensed. Pharmacists must perform calculations
842 and measurements to obtain, theoretically, 100% of the amount of each ingredient in
843 compounded formulations. Calculations must account for the active ingredient, or active
844 moiety, and water content of drug substances, which includes that in the chemical
845 formulas of hydrates. Official drug substances and added substances must meet the
846 requirements in general chapter Loss on Drying 731 , which must be included in the
847 calculations of amounts and concentrations of ingredients. The pharmacist should
848 consider the effect of ambient humidity on the gain or loss of water from drugs and
849 added substances in containers subjected to intermittent opening over prolonged
850 storage. Each container should be opened for the shortest duration necessary and then
851 closed tightly immediately after use.
852 The nature of the drug substance to be weighed and used in compounding a
853 prescription must be known. If the substance is a hydrate, its anhydrous equivalent
854 weight may need to be calculated. On the other hand, if there is adsorbed moisture
855 present that is either specified on a Certificate of Analysis (CoA) or that is determined in
856 the pharmacy immediately before the drug substance is used in the preparation (see
857 chapter 731 ), this information must be used when calculating the amount of drug
858 substance that is to be weighed to determine the exact amount of anhydrous drug
859 substance required.
860 There are cases in which the required amount of a dose is specified in terms of a
861 cation (e.g., Li+), an anion (e.g., F−), or a molecule (e.g., theophylline in aminophylline).
862 In these instances, the drug substance weighed is a salt or complex, a portion of which
863 represents the pharmacologically active moiety. Thus, the exact amount of such
864 substances weighed must be calculated on the basis of the required quantity of the
865 pharmacological moiety.
866 The following formula may be used to calculate the theoretical weight of an ingredient
867 in a compounded preparation:
868 W = AB/CD
869
870 W = actual weighed amount
871 A = prescribed or pharmacist-determined weight of the active or functional moiety of
872 drug or added substance
873 B = molecular weight (MW) of the ingredient, including waters of hydration for hydrous
874 ingredients
875 C = MW of the active or functional moiety of a drug or added substance that is
876 provided in the MW of the weighed ingredient
877 D = the fraction of dry weight when the percent by weight of adsorbed moisture
878 content is known from the loss on drying procedure (see chapter 731 ) or from the
879 CoA. The CoA should be lot specific.
880 2.1 Active Ingredients
881 2.1.1 CALCULATING DRUGS DOSED AS SALT FORM AND HYDRATE
882 Examples—Drugs dosed as salt form and hydrate
883 1. Drugs dosed as salt form and hydrate
884 Triturate morphine sulfate and lactose to obtain 10 g in which there are 30 mg of
885 morphine sulfate for each 200 mg of the morphine–lactose mixture. [NOTE—Morphine is
886 dosed as the morphine sulfate, which is the pentahydrate.]
887
888 W = weight of morphine sulfate (g)
889 A = weight of morphine sulfate pentahydrate in the prescription, 1.5 g
890 B = MW of morphine sulfate pentahydrate, 759 g/mol
891 C = MW of morphine sulfate pentahydrate, 759 g/mol
892 D = 1.0
893 To solve the equation:
894 W = (1.5 g × 759 g/mol)/(759 g/mol × 1) = 1.5 g of morphine sulfate pentahydrate
895 2. Active drug moiety and correction for moisture
896 Accurately weigh an amount of aminophylline to obtain 250 mg of anhydrous
897 theophylline. [NOTE—In this example, the powdered aminophylline dihydrate weighed
898 contains 0.4% w/w absorbed moisture as stated in the CoA received by the pharmacy.]
899 W = AB/CD
900
901 W = weight of aminophylline dihydrate (mg)
902 A = weight of anhydrous theophylline, 250 mg
903 B = MW of aminophylline dihydrate, 456 g/mol
904 C = MW of anhydrous theophylline, 360 g/mol
905 D = 0.996
906 [NOTE—One mol of aminophylline contains 2 mol of theophylline. Theophylline has a
907 MW of 180.]
908 To solve the equation:
909 W = (250 mg × 456 g/mol)/(360 g/mol × 0.996) = 318 mg of aminophylline dihydrate
910 2.2 Hydrates, Salts, and Esters
911 Frequently, for stability or other reasons such as taste or solubility, the base form of a
912 drug is administered in another form such as a salt or an ester. This altered form of the
913 drug usually has a different MW, and at times it may be useful to determine the amount
914 of the base form of the drug in the altered form.
915 2.2.1 CALCULATING HYDRATES, SALTS, AND ESTERS
916 Examples—Hydrates, salts, and esters
917 1. Hydrates
918 If a prescription for 100 g of lidocaine hydrochloride 2% gel is to be made, 2 g of
919 anhydrous lidocaine hydrochloride could be used, or the equivalent amount of lidocaine
920 hydrochloride monohydrate could be calculated as follows:
921
922 W = weight of lidocaine hydrochloride monohydrate (g)
923 A = weight of anhydrous lidocaine hydrochloride in the prescription, 2 g
924 B = MW of lidocaine hydrochloride monohydrate, 288.81 g/mol
925 C = MW of anhydrous lidocaine hydrochloride, 270.80 g/mol
926 D = 1.0
927 To solve the equation:
928 W = (2 g × 288.81 g/mol)/(270.80 g/mol × 1) = 2.133 g of lidocaine hydrochloride
929 monohydrate
930 2. Salts
931 A prescription calls for 10 mL of a fentanyl topical gel at a concentration 50 µg
932 fentanyl/0.1 mL prepared from fentanyl citrate. The amount of fentanyl citrate required
933 for the preparation could be calculated as follows:
934 Amount of fentanyl needed for the preparation:
935 (50 µg fentanyl/0.1 mL) × 10 mL = 5000 µg of fentanyl
936
937 W = weight of fentanyl citrate in the prescription (µg)
938 A = weight of fentanyl in the prescription, 5000 µg
939 B = MW of fentanyl citrate, 528.59 g/mol
940 C = MW of fentanyl, 336.47 g/mol
941 D = 1.0
942 To solve the equation:
943 W = (5000 µg × 528.59 g/mol)/(336.47 g/mol × 1) = 7855 µg of fentanyl citrate
944 3. Esters
945 The amount of cefuroxime axetil contained in a single 250-mg cefuroxime tablet can
946 be calculated as follows:
947
948 W = weight of cefuroxime axetil in tablet (mg)
949 A = weight of cefuroxime in the prescription, 250 mg
950 B = MW of cefuroxime axetil, 510.47 mg/mmol
951 C = MW of cefuroxime, 424.39 mg/mmol
952 D = 1.0
953 To solve the equation:
954 W = (250 mg × 510.47 g/mol)/(424.39 g/mol × 1) = 300 mg of cefuroxime axetil
955
956 3. DOSAGE CALCULATIONS
957 3.1 Dosing by Weight
958 Doses are frequently expressed as mg of drug per kg of body weight per a dosing
959 interval.
960 3.1.1 CALCULATING DOSING BY WEIGHT
961 Example—Dosing by weight
962 A physician orders azithromycin for oral suspension at a dose of 15 mg/kg/day, divided
963 every 12 h, for a child that weighs 36 lb. Calculate the volume of oral suspension, in mL,
964 that should be administered for each dose of a 200-mg/5-mL suspension as follows:

965 a. Calculate the child's weight in kg:

966 36 lb × kg/2.2 lb = 16.4 kg

967 b. Multiply the weight, in kg, by the dosing rate:

968 16.4 kg × 15 mg/kg/day = 246 mg/day

969 c. Divide the total daily dose by the number of doses/day:

970 246 mg/2 doses = 123 mg/dose

971 d. Calculate the volume of each dose using ratio and proportion:

972 (123 mg/dose)/(200 mg/5 mL) = 3.1 mL/dose

973 Some calculations may also be completed using dimensional units analysis (DUA).
974 The DUA should begin at the left end with a factor containing the numerator answer
975 units. All units other than those in the answer should cancel. If using DUA, the
976 preceding equation would be as follows:
977
978 3.2 Dosing by Body Surface Area (Humans)
979 Some medications, including chemotherapeutic agents, require dosing by body
980 surface area (BSA). The dose is expressed as amount of drug per meter squared (m2).
981 BSA may be calculated using the following formulas:

982
983 3.2.1 CALCULATING BY BODY SURFACE AREA (HUMAN)
984 Example—Dosing by BSA (humans)
985 A physician orders rituximab at a dose of 375 mg/m2 every week for 6 weeks for a
986 patient who is 6 ft 2 in tall and weighs 183 lb. Calculate the volume, in mL, of 10-mg/mL
987 rituximab injection needed to make each IV infusion dose as follows:

988 a. Calculate the patient’s BSA:

989

990 b. Multiply the BSA by the dosing rate:

991 2.08 m2 × 375 mg/m2 = 780 mg/dose

992 c. Calculate the volume of each dose using ratio and proportion:

993 (780 mg/dose)/(10 mg/mL) = 78 mL/dose

994 The preceding calculation may also be completed using DUA as follows:

995
996 3.3 Dosing By Body Surface Area (Animals)
997 BSA for cats and dogs may be calculated using the following formulas. For other
998 animals, consult an appropriate veterinary medicine reference.
999 Body surface area for cats:
1000 BSA (m2) = {10 × [body weight (g)]0.667}/10,000
1001 Body surface area for dogs:
1002 BSA (m2) = {10.1 × [body weight (g)]0.667}/10,000
1003 3.3.1 CALCULATING DOSING BY BODY SURFACE AREA (ANIMALS)
1004 Example—Dosing by BSA (animals)
1005 A veterinarian orders oral cyclophosphamide therapy at a dose of 50 mg/m2 for a cat
1006 who weighs 5.8 kg. Calculate the dose of cyclophosphamide as follows:

1007 a. Calculate the cat’s BSA:

1008 BSA (m2) = [10 × (5800 g)0.667]/10,000 = 0.324 m2

1009 b. Multiply the BSA by the dosing rate:

1010 0.324 m2 × 50 mg/m2 = 16.2 mg

1011
1012 4. USE OF POTENCY UNITS
1013 Because some substances cannot be completely characterized by chemical and
1014 physical means, it may be necessary to express quantities of activity in biological units
1015 of potency (see the USP General Notices and Requirements 5.50.10, Units of Potency
1016 (Biological)).
1017 4.1 Calculating by Use of Potency Units
1018 Examples—Use of potency units
1019 1. Potency units-to-milligrams conversion
1020 A dose of penicillin G benzathine for streptococcal infection is 1.2 million units
1021 administered intramuscularly. If a specific product contains 1180 units/mg, calculate the
1022 amount, in mg, of penicillin G benzathine in the dose as follows:
1023 (1,200,000 units)/(1180 units/mg) = 1017 mg of penicillin G benazathine
1024 2. Potency units-to-milligrams conversion
1025 A prescription calls for 60 g of an ointment containing 150,000 units of nystatin per
1026 gram. Calculate the quantity of nystatin with a potency of 4400 units/mg that should be
1027 weighed for the prescription as follows:
1028 60 g × (150,000 units of nystatin/g) = 9,000,000 units
1029 9,000,000 units/(4400 units/mg) = 2045 mg of nystatin
1030
1031 5. VOLUME AND WEIGHT SUMS
1032 Weights are additive in most mixtures of liquids, semisolids, and solids. Volumes in
1033 mixtures of miscible solutions and pure liquids may or may not be additive, based
1034 primarily on the effects of volume proportions and intermolecular hydrogen bonding. For
1035 example, mixtures containing equal or near-equal volumes of water and ethanol (and
1036 other miscible mono-hydroxy alcohols) will be exothermic and result in a volume
1037 contraction of <5%, e.g., 50 mL water + 50 mL ethanol yield 97–98 mL at 20°–25°.
1038 Negligible volume contraction occurs between water and polyhydroxy or polyhydric
1039 alcohols, e.g., glycerin and propylene glycol. Volumes are additive with usually
1040 negligible error in aqueous mixtures that contain <10% of mono-hydroxy alcohols, i.e.,
1041 there is <0.5% volume contraction.
1042
1043 6. DENSITY AND SPECIFIC GRAVITY
1044 Density is defined as the mass of a substance in air at a specific temperature (typically
1045 25°) per unit volume of that substance at the same temperature. Density may be
1046 calculated with the following equation:
1047 Density = (mass of substance/volume of substance) at a particular temperature and
1048 pressure
1049 Specific gravity (SG) is the unitless ratio of the density of a substance to the density of
1050 water at 4°, or [(g of substance/mL)/1.00 g/mL]. Alternatively, SG can be calculated at a
1051 particular temperature in some common units of density from density of substance per
1052 density of water.
1053 SG may be calculated with the following equation:
1054 SG = (weight of the substance)/(weight of an equal volume of water)
1055 6.1 Calculating Density and Specific Gravity
1056 Examples—Density and specific gravity
1057 1. Density calculation
1058 2.3 g of activated charcoal powder occupies a bulk volume of 5.2 mL at 20° and 1 atm.
1059 The density of activated charcoal powder can be calculated as follows:
1060 Density = 2.3 g/5.2 mL = 0.44 g/mL
1061 2. SG calculation
1062 125.0 g of glycerin occupies a volume of 99.0 mL at 25°. [NOTE—The density of water
1063 at 25° is 0.997 g/mL.] The SG of glycerin can be calculated as follows:
1064 SG = (125 g/99 mL)/(0.997 g/mL) = 1.266
1065 3. Concentrated acid calculation
1066 Hydrochloric acid is approximately a 37% w/w solution of hydrochloric acid in water.
1067 Calculate the amount, in g, of hydrochloric acid contained in 75.0 mL of hydrochloric
1068 acid as follows. [NOTE—The SG of hydrochloric acid is 1.18.]
1069 37% w/w × 1.18 = 43.7% w/v
1070 (43.7 g/100 mL) × 75 mL = 32.8 g of hydrochloric acid
1071
1072 7. MILLIEQUIVALENTS AND MILLIMOLES
1073 [NOTE—This section addresses milliequivalents (mEq) and millimoles (mmol) as they
1074 apply to electrolytes for dosage calculations. See also the 8. Concentrations
1075 Expressions section of this chapter.]
1076 The quantities of electrolytes administered to patients are usually expressed in terms
1077 of mEq. Weight units such as mg or g are not often used for electrolytes because the
1078 electrical properties of ions are best expressed as mEq. An equivalent (Eq) is the weight
1079 of a substance that supplies 1 unit of charge. An equivalent weight is the weight, in g, of
1080 an atom or radical, divided by the valence of the atom or radical. A mEq is 1/1000th of an
1081 Eq. The equivalent weight of a compound may be determined by dividing its formula or
1082 MW in g by the valence of its largest valence ion.
1083 A mole equals one gram-atomic weight or gram-molecular weight of a substance. A
1084 millimole equals 1/1000th of a mole.
1085 7.1 Calculating Milliequivalents and Millimoles
1086 Examples—Milliequivalents and millimoles
1087 1. Calculate the mEq weight of calcium. [NOTE—Calcium has a MW of 40.08, and the
1088 valence of calcium is 2+.]
1089 Eq weight = 40.08 g/2 = 20.04 g
1090 mEq weight = 20.04 g/1000 = 0.02004 g = 20.04 mg
1091 2. Calculate the quantity, in mEq, of potassium in a 250-mg Penicillin V Potassium
1092 Tablet. [NOTE—Penicillin V potassium has a MW of 388.48 g, there is one potassium
1093 atom in the molecule, and the valence of potassium is 1+.]
1094 Eq weight = 388.48 g/1 = 388.48 g
1095 mEq weight = 388.48 g/1000 = 0.38848 g = 388.48 mg
1096 (250 mg/tablet)/(388.48 mg/mEq) = 0.644 mEq of potassium/tablet
1097 3. Calculate the mEq of magnesium and sulfate in a 2-mL dose of 50% Magnesium
1098 Sulfate Injection. [NOTE—Magnesium sulfate (MgSO4 · 7H2O) has a MW of 246.47, and
1099 the highest valence ion is magnesium 2+ and sulfate 2-.]
1100 (50 g/100 mL) × (2 mL/dose) = 1 g/dose
1101 Eq weight = 246.47 g/2 = 123.24 g/Eq
1102 (1g/dose)/(123.24 g/Eq) = 0.008114 Eq = 8.114 mEq of both magnesium and sulfate per
1103 dose
1104 This problem may also be worked using DUA as follows:

1105
1106 4. A vial of sodium chloride injection contains 3 mEq/mL of sodium chloride. Calculate
1107 the strength, in % w/v, of the injection. [NOTE—Sodium chloride has a MW of 58.44.]

1108
1109 (0.1753 g/mL) × 100 mL = 17.53 g in 100 mL = 17.53% w/v
1110 5. Calculate the weight of potassium in mmol. [NOTE—Potassium has a MW of 39.1.]
1111 The weight of 1 mol is 39.1 g and the weight in mmol is:
1112 39.1 g/1000 = 0.0391 g or 39.1 mg
1113 6. Calculate the mmol of penicillin V potassium in a 250-mg Penicillin V Potassium
1114 Tablet. [NOTE—Penicillin V potassium has a MW of 388.48.]
1115 The weight of 1 mol is 388.48 g, and the weight of 1 mmol is:
1116 388.48 g/1000 = 0.38848 g or 388.48 mg
1117
1118
1119 8. CONCENTRATION EXPRESSIONS
1120 The concentration expressions in this section refer to homogeneous mixtures of the
1121 following states of matter at a temperature of 20°–30° and pressure of 1 atm (29.92 in
1122 Hg, 760 mm Hg, 101.3 kPa, 1013.3 mb): gas in gas, gas in liquid, liquid in liquid, liquid
1123 in semisolid, solid in liquid, solid in semisolid, and solid in solid. Concentration
1124 expressions used in pharmacy practice and pharmaceutical research include, but are
1125 not limited to, those listed in Table 1. Common metric drug strength and clinical
1126 concentrations include, for example, µg/mL, mg/dL, g or mg per L, and ng/µL (see
1127 General Notices and Requirements 8.240, Weights and Measures).
1128 Table 1

Title Abbreviation Definition

Mass in None is Mass of a dispersed or dissolved ingredient per volume
volume ratios standard amount of mixtures containing that ingredient
mEqa per mEq/volume mEq of an electrolyte or salt per unit of volume of
volume unit solutions containing that electrolyte or salt
Molality m molb of a solute/kg of a solvent containing that solutec
Molarity M mol of a solute/L of a solvent containing that soluted
Equivalents (Eqf) of a solute/L of a solvent containing
Normality e
N that soluteg
Parts of a gas, liquid, or solid per 1 million part of
Parts per another gas, liquid, or solid containing the first gas,
million ppm liquid, or solid
% volume in mL of liquid per 100 mL of a solvent containing that
volume % v/v liquid
% weight in g of a solute per 100 mL of a solvent containing that
volume % w/v solute
% weight in g of a solute per 100 g of a mixture containing that
weight % w/w solute
1 part of an ingredient per Rh parts of a mixture
1:R containing that ingredient
1 part of an ingredient in Rh parts of a mixture
1 in R containing that ingredient
Xh parts of one ingredient per Yh parts of another
Ratio strength X:Y ingredient in a mixture
a 
1 mEq = Eq/1000.
b 
The abbreviation for mole is mol.
 Title Abbreviation Definition
c 
1 mol of solute per 1 kg of solvent is a 1 molal (1 m) solution.
d 
1 mol of solute per 1 L of solution of that solute is a 1 molar (1 M) solution.
e 
Normality = (Molarity × largest valence ion of a compound), e.g., (18 M H2SO4 × 2) = 36 N H2SO4, where
2 derives from the 2− valence of SO4.
f 
Eq of a compound = (1 mol × largest valence ion of a compound), e.g., 1 mol of lithium citrate = 3 Eq of
lithium citrate; 1 mol of Ca(gluconate)2 = 2 Eq of Ca(gluconate)2; and 1 mol of KCl = 1 Eq of KCl.
g 
1 Eq of solute per 1 L of solution of that solute is a 1 normal (1 N) solution.
h 
R, X, and Y are whole numbers.

1129 8.1 Calculating Normality

1130 Example—Normality
1131 Calculate the amount of sodium bicarbonate powder needed to prepare 50 mL of a
1132 0.07 N solution of sodium bicarbonate (NaHCO3). [NOTE—Sodium bicarbonate has a MW
1133 of 84.01.] In an acid or base reaction, because NaHCO3 may act as an acid by giving up
1134 one proton, or as a base by accepting one proton, one Eq of NaHCO3 is contained in
1135 each mole of NaHCO3

1136
1137 8.2 Calculating Percentage Concentrations
1138 Percentage concentrations of solutions and other homogeneous mixtures are usually
1139 expressed in one of three common forms in which numerator and denominator
1140 quantities are in g and mL measurement units.

1141 1. Volume percent (% v/v) = (volume of liquid solute/volume of solution or

1142 suspension) × 100

1143 or % v/v = mL of liquid solute in 100 mL of solution or suspension

1144 2. Weight percent (% w/w) = (weight of solute/weight of mixture) × 100

1145 or % w/w = g of ingredient in 100 g of mixture

1146 3. Weight in volume percent (% w/v) = (weight of solute/volume of solution or

1147 suspension) × 100

1148 or % w/v = g of solute in 100 mL of solution or suspension

1149 The preceding three equations may be used to calculate any one of the three values
1150 (i.e., weights, volumes, or percentages) in a given equation if the other two values are
1151 known (see also General Notices and Requirements 8.140, Percentage
1152 Concentrations).
1153 Examples—Percentage concentrations
1154 1. Weight percent
1155 A prescription order reads as follows (see Table 2):
1156 Table 2

Zinc oxide 7.5 g

Calamine 7.5 g
Starch 15 g
White petrolatum 30 g
1157 Calculate the percentage concentration for each of the four components using the
1158 preceding weight percent equation as follows:

1159 a. The total weight of ointment = 7.5 g + 7.5 g + 15 g + 30 g = 60.0 g
1160 b. The weight percent of zinc oxide = (7.5 g of zinc oxide/60 g of ointment) × 100%
1161 = 12.5%
1162 c. The weight percent of calamine = (7.5 g of calamine/60 g of ointment) × 100% =
1163 12.5%
1164 d. The weight percent of starch = (15 g of starch/60 g of ointment) × 100% = 25%
1165 e. The weight percent of white petrolatum = (30 g of white petrolatum/60 g of
1166 ointment) × 100% = 50%

1167 2. Volume percent

1168 A prescription order reads as follows:
1169 Rx: Eucalyptus Oil 3% v/v in Mineral Oil.
1170 Dispense 30 mL.
1171 Calculate the quantities of ingredients in this prescription using the volume percent
1172 equation as follows:

1173 a. The amount of eucalyptus oil.

1174 3% v/v = (volume of oil in mL/30.0 mL) × 100%

1175 volume in oil = 0.9 mL of eucalyptus oil

1176 b. The amount of mineral oil.

1177 30 mL − 0.9 mL = 29.1 mL of mineral oil

1178 8.3 Conversions of Concentration Expressions

1179 8.3.1 SOLID-IN-LIQUID SOLUTION CONVERSIONS
1180 The calculations used to convert from percent weight in volume, % w/v, to other
1181 concentrations and vice versa, using the same densities and formula or molecular
1182 weights, are illustrated as follows for calcium chloride, magnesium sulfate, and
1183 potassium chloride solutions in water.
1184 8.3.1.1 Calculating solid-in-liquid conversions:
1185 Examples—Solid-in-liquid conversions
1186 1. Convert 10% w/v calcium chloride (CaCl2 · 2H2O) to molality (m). [NOTE—Calcium
1187 chloride has a MW of 147.01 g; 10% w/v solution has a density of 1.087 g/mL.]
1188 10% w/v = 10 g of calcium/100 mL of solution
1189 Using the density of the solution:
1190 100 mL of solution × 1.087 g/mL = 108.7 g of solution
1191 108.7 g of solution − 10 g of calcium chloride = 98.7 g of water = 0.0987 kg of water
1192 10 g of calcium chloride/(147.01 g of calcium chloride/mol of calcium chloride) = 0.068
1193 mol of calcium chloride
1194 0.068 mol of calcium chloride/0.0987 kg of water = 0.689 m
1195 2. Convert 50% w/v magnesium sulfate (MgSO4 · 7H2O) to molarity (M). [NOTE—
1196 Magnesium sulfate has a MW of 246.47 g.]

1197
1198 3. Convert 10% w/v calcium chloride (CaCl2 · 2H2O) to normality (N).

1199
1200 *2 Eq/mol derived from the 2+ valence of calcium
1201 4. Convert 10% w/v calcium chloride (CaCl2 · 2H2O) to mEq/mL.

1202
1203 5. Convert 0.1% w/v calcium chloride (CaCl2 · 2H2O) to ppm.
1204 (0.1 g/100 mL) × (1 × 106 ppm) = 1000 ppm
1205 6. Convert 33% w/v potassium chloride (KCl) to 1:R ratio strength.
1206 (1/R) = (33 g/100 mL)
1207 R = 3.03
1208 1:R = 1:3
1209 8.3.2 LIQUID-IN-LIQUID SOLUTION CONVERSIONS
1210 The calculations used to convert from percent weight in weight, % w/w, and volume in
1211 volume, % v/v, to other concentrations and vice versa using the same densities and
1212 formula or MWs, are illustrated for glycerin and isopropyl alcohol in water. Besides
1213 liquid-in-semisolid, solid-in-semisolid, and solid-in-solid mixtures, % w/w is used for
1214 viscous liquids, such as coal tar, glycerin, and concentrated acids.
1215 8.3.2.1 Converting liquid-in-liquid solutions:
1216 Examples—Liquid-in-liquid conversions
1217 1. Convert 50% w/w glycerin to % w/v. [NOTE—50% w/w glycerin has a density of
1218 1.13 g/mL.]
1219 (50 g/100 g) × (1.13 g/mL) = 56.5 g
1220 56.5 g/100 mL = 56.5% w/v
1221 2. Convert 70% v/v isopropyl alcohol to % w/w. [NOTE—Isopropyl alcohol has a density
1222 of 0.79 g/mL, and 70% v/v isopropyl alcohol has a density of 0.85 g/mL.]
1223 70 mL of isopropyl alcohol × (0.79 g/mL) = 55.3 g of isopropyl alcohol
1224 100 mL of solution × (0.85 g/mL) = 85 g of solution
1225 (55.3 g of isopropyl alcohol/85 g of solution) × 100 = 65.06% w/w
1226 3. Convert 70% v/v isopropyl alcohol to % w/v. The following values are from example
1227 2.
1228 55.3 g of isopropyl alcohol/100 mL of solution = 55.3% w/v
1229 4. Convert 50% w/w glycerin to molality (m). [NOTE—Glycerin has a MW of 92.1.]
1230 50 g of glycerin/(92.1 g/mol) = 0.543 mol of glycerin
1231 100 g of solution − 50 g of glycerin = 50 g of water = 0.05 kg of water
1232 (0.543 mol of glycerin/0.05 kg of water) = 10.86 m
1233 5. Convert 70% v/v isopropyl alcohol to molality (m). [NOTE—Isopropyl alcohol has a
1234 density of 0.79 g/mL and a MW of 60.1; 70% v/v isopropyl alcohol has a density of
1235 0.85 g/mL.]
1236 70 mL of isopropyl alcohol × (0.79 g/mL) = 55.3 g of isopropyl alcohol
1237 100 mL of solution × (0.85 g/mL) = 85 g of solution
1238 (85 g of solution − 55.3 g of isopropyl alcohol) = 29.7 g of water = 0.0297 kg of water
1239 55.3 g of isopropyl alcohol/(60.1 g/mol) = 0.92 mol of isopropyl alcohol
1240 (0.92 mol of isopropyl alcohol/0.0297 kg of water) = 30.98 m
1241 6. Convert 50% w/w glycerin to molarity (M). [NOTE—Glycerin has a MW of 92.1 g.]
1242 From example 1, 50% w/w glycerin = 56.5% w/v glycerin
1243 (56.5 g/100 mL) × (mol/92.1 g) × (1000 mL/L) = 6.13 M
1244 7. Convert 50% w/w glycerin to % v/v. [NOTE—50% w/w of glycerin has a density of
1245 1.13 g/mL; 100% glycerin has a density of 1.26 g/mL.]
1246 50 g of glycerin/(1.26 g/mL) = 39.7 mL of glycerin
1247 100 g of solution/(1.13 g/mL) = 88.5 mL of solution
1248 (39.7 mL of glycerin/88.5 mL of solution) × 100% = 44.8% v/v
1249 9. Convert 50% w/w glycerin to 1 in R ratio strength.
1250 1/R = (50 g of glycerin/100 g of solution)
1251 R=2
1252 1 in R = 1 in 2
1253 8.3.3 SOLID AND SEMISOLID IN SOLID AND SEMISOLID MIXTURE CONVERSIONS
1254 The calculations used to convert from percent weight in weight (% w/w) to ppm and
1255 ratio strengths are illustrated as follows for fluocinonide and tolnaftate in topical
1256 semisolids and powders.
1257 8.3.3.1 Calculating solid and semisolid in solid and semisolid mixture
1258 conversions:
1259 Examples—Solid and semisolid in solid and semisolid mixture conversions
1260 1. Convert 0.05% w/w fluocinonide ointment to ppm.
1261 (0.05 g/100 g) × (1 × 106 ppm) = 500 ppm
1262 2. Convert 1.5% w/w tolnaftate powder to 1:R ratio strength.
1263 1/R = (1.5 g of tolnaftate/100 g of powder)
1264 R = 67
1265 1:R = 1:67
1266 3. Convert 1% w/w tolnaftate in talcum powder to X:Y ratio strength.
1267 100 g of powder − 1 g of tolnaftate = 99 g of talcum
1268 X:Y = 1 g of tolnaftate:99 g of talcum
1269 8.4 Dilution and Concentration
1270 A more concentrated solution can be diluted to a lower concentration to obtain
1271 appropriate strength and precision when compounding preparations. Powders and
1272 semisolid mixtures can be triturated or mixed to achieve lower concentrations. The
1273 amount of an ingredient in the diluted mixture is the same as that in the portion of the
1274 more concentrated source used to make the dilution; thus, the following equation can be
1275 applied to dilution problems (Q1)(C1) = (Q2)(C2), where Q1 and Q2 are the quantity of
1276 solutions 1 and 2, respectively, and C1 and C2 are concentrations of solutions 1 and 2,
1277 respectively. Any quantities and concentration terms may be used but the units of those
1278 terms must be the same on both sides of the equation.
1279 8.4.1 CALCULATING DILUTION AND CONCENTRATION
1280 Examples—Dilutions and fortifications
1281 1. Semisolid dilution
1282 Calculate the quantity (Q2), in g, of diluent that must be added to 60 g of a 10% w/w
1283 ointment to make a 5% w/w ointment.
1284 (Q1) = 60 g, (C1) = 10% w/w, and (C2) = 5% w/w
1285 60 g × 10% w/w = (Q2) × 5% w/w
1286 (Q2) = 120 g
1287 120 g − 60 g = 60 g of diluent to be added
1288 2. Solid dilution
1289 Calculate the amount of diluent that should be added to 10 g of a trituration (1 in 100)
1290 to make a mixture that contains 1 mg of drug in each 10 g of the final mixture.
1291 Convert mg to g: 1 mg of drug = 0.001 g of drug
1292 10 g of mixture should contain 0.001 g of drug
1293 (Q1) = 10 g, (C1) = (1 in 100), and (C2) = (0.001 in 10)
1294 10 g × (1/100) = (Q2) × (0.001/10)
1295 (Q2) = 1000 g
1296 Because the final mixture of 1000 g contains 10 g of the trituration, 990 g (or 1000 g −
1297 10 g) of diluent is required to prepare the mixture at a concentration of 0.001 g of drug in
1298 each 10 g.
1299 3. Liquid dilution
1300 Calculate the percentage strength (C2) of a solution obtained by diluting 400 mL of a
1301 5.0% w/v solution to 800 mL.
1302 (Q1) = 400 mL, (C1) = 5.0% w/v, and (Q2) = 800 mL
1303 400 mL × 5% w/v = 800 mL × (C2)
1304 (C2) = 2.5% w/v
1305 4. Liquid fortification
1306 Calculate the additional amount, in g, of codeine phosphate that need to be added to
1307 180 mL of a 12 mg/5 mL elixir of acetaminophen with codeine to have a final
1308 concentration of 30 mg/5 mL of codeine phosphate.
1309 Amount to add = Total amount required − Amount present
1310 Total amount required: (30 mg/5 mL) × 180 mL = 1080 mg of codeine phosphate
1311 Amount present = (12 mg of codeine/5 mL) × 180 mL = 432 mg of codeine phosphate
1312 Amount to add: 1080 mg − 432 mg = 648 mg of codeine phosphate
1313
1314 9. ALCOHOL
1315 To achieve compliance with the statements in the General Notices and Requirements
1316 about Alcohol and the USP monograph for Alcohol, some conventions and special
1317 calculations are needed. See General Notices and Requirements 5.20.20.1, In
1318 Compounded Preparations, 8.30, Alcohol Content, and 10.40.80, Labeling Alcohol for
1319 information. The USP monograph for Alcohol states that it contains 92.3%–93.8% by
1320 weight corresponding to 94.9%–96.0% by volume of alcohol (C2H5OH) at 15.56°. The
1321 percent concentration for alcohol is generally taken to be 95% v/v of alcohol (C2H5OH) in
1322 water.
1323 In summary:

1324  When the word alcohol is written on a prescription order or in a formula, as for
1325 example “alcohol 10 mL” or “dissolve in 5 mL of alcohol”, the compounder
1326 should use the Alcohol, USP [that is 95% alcohol (C2H5OH)].
1327  When the word alcohol is written with a percent, for example “alcohol 20%”, this
1328 means 20% v/v of alcohol (C2H5OH). If this percent is on a label of a commercial
1329 product, it means the product contains 20% v/v alcohol (C2H5OH). If this is part
1330 of a compounding formula, it means the compounder must add the equivalent
1331 of 20% v/v alcohol (C2H5OH), which may require special calculations.
1332  Labels of products and compounded preparations are to include the content of
1333 alcohol (C2H5OH) in % v/v. For compounded preparations, this value must often
1334 be calculated based on the volume(s) of alcohol-containing ingredients added.

1335 For calculations when preparing compounded drug preparations using Alcohol, USP,
1336 the first step is to determine the quantity, in mL, of alcohol needed, and the second step
1337 is to determine the % v/v of alcohol (C2H5OH) in the final preparation so that it can be
1338 properly labeled.
1339 9.1 Calculating Alcohol
1340 Examples—Alcohol
1341 1. Determine the quantity of alcohol needed for the prescription (see Table 3):
1342 Table 3

Clindamycin 1%
Alcohol 15%
Propylene glycol 5%
Purified water, a sufficient quantity to make 60 mL

1343 a. In this prescription order, the alcohol 15% means the preparation contains 15%
1344 v/v of alcohol (C2H5OH).
1345 b. For 60 mL of preparation, calculate the quantity of alcohol (C2H5OH) needed:

1346 15% v/v × 60 mL = 9 mL of alcohol

1347 c. Because the source of alcohol (C2H5OH) is Alcohol, USP, calculate the volume, in
1348 mL, of Alcohol, USP needed to give 9 mL of alcohol (C2H5OH):

1349 9 mL alcohol/95% v/v Alcohol, USP = 9.5 mL of Alcohol, USP

1350 Therefore, add 9.5 mL of Alcohol, USP to this preparation.

1351 d. Determine the % v/v alcohol content for labeling.

1352 Because labeling of alcohol is in % v/v of alcohol (C2H5OH), the alcohol content
1353 of this preparation would be labeled: Alcohol 15%.

1354 2. Determine the alcohol content, in % v/v, for the prescription (see Table 4):
1355 Table 4

Castor oil 40 mL
Acacia As needed
Alcohol 15 mL
Cherry syrup 20 mL
 Purified water, a sufficient quantity to make 100 mL
1356 Because the USP monograph for Alcohol is to be used when alcohol is called for in
1357 formulas, measure 15 mL of Alcohol, USP.
1358 95% Alcohol, USP × 15 mL = 14.25 mL of alcohol
1359 14.25 mL of alcohol/100 mL of preparation = 14.25% alcohol
1360
1361 10. ALLIGATION ALTERNATE AND ALGEBRA METHODS
1362 10.1 Alligation Alternate
1363 Alligation is a method of determining the proportions in which substances of different
1364 strengths are mixed to yield a desired strength or concentration. Once the proportion is
1365 found, the calculation may be performed to find the exact amounts of substances
1366 required.
1367 Set up the problem as follows.

1368 1. Place the desired percentage or concentration in the center.

1369 2. Place the percentage of the substance with the lower strength on the lower left-
1370 hand side.
1371 3. Place the percentage of the substance with the higher strength on the upper left-
1372 hand side.
1373 4. Subtract the lower percentage from the desired percentage, and place the
1374 obtained difference on the upper right-hand side.
1375 5. Subtract the desired percentage from the higher percentage, and place the
1376 obtained difference on the lower right-hand side.

1377 The results on the right side determine how many parts of the two different percentage
1378 strengths should be mixed to produce the desired percentage strength of a drug
1379 mixture. The total parts will equal the final weight or volume of the preparation.
1380 10.1.1 CALCULATING BY USING THE ALLIGATION ALTERNATE
1381 Examples—Alligation alternate
1382 1. Determine the amount of ointment containing 12% drug concentration and the
1383 amount of ointment containing 16% drug concentration must be used to make 1 kg of a
1384 preparation containing a 12.5% drug concentration.

1385
1386 In a total of 4 parts of 12.5% preparation, 3.5 parts of 12% ointment and 0.5 parts of
1387 16% ointment are needed.
1388 4 parts correspond to 1 kg or 1000 g.
1389 1 part corresponds to 250 g.
1390 3.5 parts correspond to 3.5 × 250 g or 875 g of 12% ointment.
1391 0.5 parts correspond to 0.5 × 250 g or 125 g of 16% ointment.
1392 2. Determine the volume, in mL, of 20% dextrose in water and 50% dextrose in water
1393 needed to make 750 mL of 35% dextrose in water.

1394

1395 In a total of 30 parts of 35% dextrose in water, 15 parts of 50% dextrose in water and
1396 15 parts of 20% dextrose in water are required.
1397 30 parts correspond to 750 mL.
1398 15 parts correspond to 375 mL.
1399 Thus, use 375 mL of the 20% solution and 375 mL of the 50% solution to prepare the
1400 preparation.
1401 10.2 Algebra Method
1402 The following algebraic equation may be used instead of alligation to solve problems of
1403 mixing two different strengths of the same ingredient:
1404 (Cs × Qs) + (Cw × Qw) = (Cf × Qf), where C is concentration or strength, Q is the quantity;
1405 and the subscript s identifies the strongest strength, w identifies the weakest strength, f
1406 represents the final mixture with a strength less than s and greater than w, (Qs + Qw) =
1407 Qf, Qs = (Qf − Qw), and Qw = (Qf − Qs).
1408 10.2.1 CALCULATING BY USING THE ALGEBRA METHOD
1409 Examples—Algebra method
1410 1. Determine the amount, in g, of 16% w/w drug ointment and 12% w/w drug ointment
1411 required to prepare 1 kg of 12.5% w/w drug ointment.
1412 (16% × Qs) + [12% × (1000 g − Qs)] = 12.5% × 1000 g
1413 16% Qs + 120 g − 12% Qs = 125 g
1414 4% Qs = 5 g
1415 Qs = 5 g/4% = 125 g of 16% ointment
1416 Qw = 1000 g − 125 g = 875 g of 12% ointment
1417 2. Determine the volume, in mL, of 10% dextrose injection and 50% dextrose injection
1418 needed to make 750 mL of 35% dextrose injection.
1419 (50% × Cs) + [10% × (750 mL − Cs)] = 35% × 750 mL
1420 50% Cs + 75 mL − 10% Cs = 262.5 mL
1421 40% Cs = 187.5 mL
1422 Cs = 187.5 mL/40% = 468.75 mL (470 mL practically)
1423 Cw = 750 mL − 468.75 mL = 281.25 mL (280 mL practically)
1424
1425 11. ALIQUOT CALCULATIONS
1426 When the quantity of drug desired requires a degree of precision in measurement that
1427 is beyond the capability of the available measuring devices, the pharmacist may use the
1428 aliquot method of measurement. It applies when potent drug substances are
1429 compounded, or when the total amount of the active drug in a single dose or
1430 individualized doses is less than the minimum accurately weighable quantity (MAWQ).
1431 Even if the amount of drug needed is greater than the MAWQ per unit, an aliquot will
1432 provide more material per unit, which will aid in handling and administration. Aliquot
1433 means “containing an exact number of times in something else”; the aliquot must be a
1434 proportional part of the total. Therefore, 5 is an aliquot part of 15, because 5 is
1435 contained exactly 3 times in 15. Both the total volume of solution or weight of powder
1436 triturate and the aliquot volume/weight should be easily and accurately measurable. If
1437 the solution or powder triturate is highly concentrated and a small error is made in
1438 measuring the aliquot, a large error can occur in the quantity of drug brought to the final
1439 formulation.
1440 Aliquots can be: solid–solid, when the active drug and the diluents are solids; solid–
1441 liquids, when the active drug is solid and is to be incorporated into a liquid preparation,
1442 such as a solution, an emulsion, or a suspension; and liquid–liquid, when the active
1443 drug is liquid and the diluents are liquids. It can be a pure liquid or a concentrated
1444 solution of a drug. Aliquots of pure liquids are relatively uncommon because few drugs
1445 are liquid in their pure state. Aliquots involving concentrated solutions are more
1446 common.
1447 There are two general methods to prepare aliquots:

1448 1. Aliquot method 1 is applicable to drugs or substances that have to be within the
1449 degree of accuracy provided by the measuring device. It is the simplest method
1450 and can be applied to solid and liquid aliquots.
1451 2. Aliquot method 2, also known as the dilution factor method, is useful when there
1452 is more flexibility in the amount of drug that may be measured.

1453 Aliquot Method 1:

1454 a. The MAWQ amount of drug is measured.

1455 b. The drug is diluted with an arbitrary amount of diluent.
1456 c. The amount of dilution that will give the desired amount of drug is calculated, and
1457 the amount is measured.

1458 Aliquot Method 2:

1459 a. The quantity of drug to be measured is determined by multiplying the amount of

1460 drug needed by an appropriately determined factor, called the dilution factor.
1461 The dilution factor must be a whole number more than or equal to the MAWQ
1462 divided by the amount of drug needed.
1463 b. An arbitrary amount of diluent is measured and added. The amount of diluent
1464 used can be determined by different methods, provided the amount of diluent
1465 chosen will give an aliquot greater than or equal to the MAWQ.
1466 c. The amount of aliquot needed is determined by multiplying the weight or volume
1467 of the dilution by the inverse of the dilution factor. Dilution factors are usually
1468 chosen to be whole numbers.

1469 The general calculations can be shown as:

1470 A/B = C/D
1471
1472 A = amount of drug desired
1473 B = amount of drug measured
1474 C = amount of drug in aliquot
1475 D = aliquot total amount
1476 11.1 Calculating Aliquots
1477 Examples—Aliquots
1478 1. Solid-in-liquid dilution (Aliquot Method 1)
1479 Prepare 100 mL of a solution containing 0.2 mg/mL of clonidine using water as the
1480 diluent. To prepare this solution, 20 mg of clonidine is needed.

1481 a. Select the weight of drug desired (A) to be equal to or greater than the MAWQ. In
1482 this situation, the MAWQ of the balance is 120 mg.
1483 b. Select the aliquot volume (D) in which the desired amount of drug (C) will be
1484 contained. This establishes the concentration of the solution to be prepared.
1485 Clonidine solubility is 1 g/13 mL, so if 5 mL is selected as the aliquot volume,
1486 the concentration in that solution will be 20 mg/5 mL. Therefore, solubility will
1487 not be a problem in this aqueous solution.
1488 c. Using the preceding formula, calculate the volume of solution (B) to be prepared.

1489 120 mg of clonidine/B = 20 mg of clonidine/5 mL of aliquot

1490 B = 30 mL
1491 d. Prepare the solution containing 120 mg of clonidine in 30 mL of Purified Water.
1492 Transfer a 5-mL aliquot from this solution to a final container, and add sufficient
1493 Purified Water to bring the formulation to a final volume of 100 mL.

1494 2. Solid-in-solid dilution (Aliquot Method 2)

1495 Prepare an individual dose of codeine phosphate 20 mg.

1496 a. Select a dilution factor that will yield a quantity that is greater than or equal to the
1497 MAWQ, and weigh this amount. In this case, the dilution factor may be greater
1498 than or equal to 6 because 6 × 20 mg = 120 mg. The smallest dilution factor that
1499 may be chosen is 6 if the MAWQ of the balance is 120 mg.
1500 b. Weigh an amount of diluent that will give an aliquot greater than or equal to the
1501 MAWQ. In this example, 600 mg of diluent is weighed.
1502 c. Mix the two powders thoroughly by geometric trituration in a mortar.
1503 d. Calculate the total weight of the dilution: 120 mg codeine phosphate + 600 mg
1504 diluent = 720 mg.
1505 e. Calculate the aliquot part of the dilution that contains 20 mg of codeine
1506 phosphate by multiplying the total weight of the dilution by the inverse of the
1507 dilution factor: 720 mg × (1/6) = 120 mg.
1508 f. Weigh this calculated amount of the dilution (120 mg) to get the desired 20 mg of
1509 codeine phosphate per dose.

1510
1511 12. POWDER VOLUME CALCULATIONS
1512 12.1 Displacement in Suspension
1513 12.1.1 CALCULATING POWDER VOLUME
1514 Examples—Powder volume
1515 1. Powder displacement in suspension
1516 The directions to reconstitute a 150 mL bottle of an amoxicillin for oral suspension of
1517 250 mg/5 mL require 111 mL of Purified Water. The physician has requested that the
1518 product be reconstituted at a concentration of 500 mg/5 mL. Calculate the amount of
1519 Purified Water required for the higher concentration.

1520 a. Calculate the volume of the suspension occupied by the amoxicillin powder:

1521 150 mL − 111 mL = 39 mL

1522 b. Calculate the quantity of amoxicillin present in the entire bottle:

1523 150 mL × (250 mg/5 mL) = 7500 mg

1524 c. Calculate the total volume of the suspension at the requested concentration (500
1525 mg/5 mL):

1526 7500 mg/(500 mg/5 mL) = 75 mL

1527 d. Calculate the volume of Purified Water needed to reconstitute the powder by
1528 subtracting the powder volume calculated in step a:

1529 75 mL − 39 mL = 36 mL of Purified Water

1530 NOTE—Such formulations may be too viscous to flow freely.

1531 2. Powder volume in drugs for injection
1532 If the powder volume of 250 mg of ceftriaxone for injection is 0.1 mL, calculate the
1533 amount of diluent that should be added to 500 mg of ceftriaxone for injection to make a
1534 suspension with a concentration of 250 mg/mL.

1535 a. Calculate the total volume of injection:

1536 500 mg/(250 mg/mL) = 2 mL

1537 b. Calculate the volume occupied by 500 mg of ceftriaxone for injection:

1538 500 mg/(250 mg/0.1 mL) = 0.2 mL

1539 c. Calculate the volume of the diluent required:

1540 (2 mL of suspension) − (0.2 mL of ceftriaxone for injection) = 1.8 mL of diluent

1541
1542 13. INTRAVENOUS FLOW OR INFUSION RATES
1543 Intravenous (IV) solutions and emulsions may be administered by gravity flow and
1544 infusion or syringe pumps. Gravity-flow IV sets are regulated by an adjustable clamp on
1545 the tubing, and the approximate flow rate is determined by counting the number of
1546 drops per 10–15 seconds, then adjusting that to a per minute rate. Manufactured IV sets
1547 are typically calibrated to deliver from 15 to 60 drops/mL, depending on the particular
1548 set.
1549 13.1 Solving by Multiple or Separate Steps
1550 As in previous sections, the following examples may be solved by multiple separate
1551 steps, or a single-DUA procedure.
1552 13.1.1 CALCULATING INTRAVENOUS FLOW OR INFUSION RATES
1553 Examples—IV or infusion rates
1554 1. An IV infusion of dextrose 5% in water with 20 mEq of potassium chloride is to be
1555 administered to a 6-year-old child at the rate of 12 mL/hour. An IV administration set
1556 that delivers 60 drops/mL is available. Calculate the flow rate in drops/minute:

1557
1558 2. A 63.6-kg patient is admitted to the Emergency Department and requires a
1559 dopamine hydrochloride infusion to maintain an adequate blood pressure. The drug is
1560 ordered at an initial rate of 2 µg/kg/minute. A 400-mg/250-mL dopamine hydrochloride
1561 injection is available. Calculate the flow rate in mL/hour to be administered by infusion
1562 pump:

1563
1564
1565 14. ISOOSMOTIC SOLUTIONS
1566 The following discussion and calculations have therapeutic implications in preparations
1567 of dosage forms intended for ophthalmic, subcutaneous, intravenous, and intrathecal
1568 administration as well as for neonatal use.
1569 14.1 Tonicity
1570 Cells of the body, such as erythrocytes, will neither swell nor shrink when placed in a
1571 solution that is isotonic with body fluids. The measurement of tonicity, however, which is
1572 a physiological property, is somewhat difficult. A 0.9% w/v sodium chloride injection,
1573 which has a freezing point (FP) of −0.52°, is both isotonic and isoosmotic with body
1574 fluids. In contrast to isotonicity, FP depression is a physical property. Some solutions
1575 that are isoosmotic with body fluids are not isotonic, because they contain solutes to
1576 which cells are freely permeable rather than semipermeable. Freely permeable solutes
1577 (e.g., boric acid and urea) can cause erythrocyte lysis, i.e., behave as if they were
1578 hypotonic in concentrations that are hyperosmotic relative to body fluids. Nevertheless,
1579 many pharmaceutical products are prepared using FP data or related sodium chloride
1580 data to prepare solutions that are isoosmotic with body fluids. A closely related topic is
1581 osmolarity (see chapter Osmolality and Osmolarity 785 ).
1582 FP data or sodium chloride equivalents of pharmaceuticals and excipients (see Table
1583 5) may be used to prepare isoosmotic solutions, as shown in the following examples.
1584 14.1.1 CALCULATING TONICITY
1585 Example—Tonicity
1586 Determine the amount of sodium chloride (NaCl) required to prepare 60 mL of an
1587 isoosmotic solution of atropine sulfate injection 0.5% using the E values and the FP
1588 depression values in Table 5.
1589 Table 5. Sodium Chloride Equivalents (E) and FP Depressions for a 1% Solution
1590 of the Drug or Excipient

Drug or Excipient E FP Depression

Atropine sulfate 0.13 0.075
Sodium chloride 1.00 0.576
1591 Using the E values:

1592 a. The total amount of substances equivalent to a 0.9% sodium chloride injection =
1593 (0.9 g/100 mL) × 60 mL = 0.54 g.
1594 b. The amount of atropine sulfate required = (0.5 g/100 mL) × 60 mL = 0.3 g.
1595 c. 1 g of atropine sulfate is equivalent to 0.13 g of sodium chloride.
1596 d. 0.3 g of atropine sulfate is equivalent to 0.3 × 0.13 g = 0.039 g of sodium chloride.
1597 e. Thus, the required amount of sodium chloride is 0.54 g − 0.039 g = 0.501 g or
1598 0.5 g.

1599 Using FP depression values:

1600 a. The FP depression required is 0.52°.

1601 b. A 1% solution of atropine sulfate causes an FP depression of 0.075°.
1602 c. A 0.5% solution of atropine sulfate causes an FP depression of 0.5 × 0.075° =
1603 0.0375°.
1604 d. The additional FP depression required is 0.52° − 0.0375° = 0.483°.
1605 e. A 1% solution of sodium chloride causes an FP depression of 0.576°.
1606 f. Therefore, an FP depression of 1° is caused by a 1%/0.576 = 1.736% solution of
1607 sodium chloride.
1608 g. 1.736% × 0.483 = 0.838% solution of sodium chloride causes an FP depression
1609 of 0.482°.
1610 h. The required amount of sodium chloride is (0.838%) × 60 mL = 0.502 g or 0.5 g.

1611
1612 15. PH AND BUFFER CALCULATIONS
1613 15.1 pH Calculations
1614 See Appendix 1 for logarithmic definitions and applications.
1615 pH = −log [H3O+], and pKa = −log ([H3O+][A−])/[HA], where [H3O+] is the hydrodium ion
1616 concentration in an aqueous solution, [A−] is the ionic form of the relevant acid, and Ka
1617 is the ionization constant of either a monoprotic acid or a particular proton from a
1618 polyprotic acid in aqueous solution. The [H+] = the antilogarithm of (−pH) or 10−pH; and Ka
1619 = the antilogarithm of (−pKa) or 10−pKa.
1620 The pH of an aqueous solution containing a weak acid may be calculated using the
1621 Henderson–Hasselbalch equation:
1622 pH = pKa + log [(base form)/(acid form)]
1623 The buffer equation symbol (↔) represents the equilibrium between conjugate base
1624 and acid forms or pairs of the same molecule. It is called the buffer equation, because
1625 small changes in the ratio of concentrations of the conjugate forms result in a
1626 logarithmically smaller change in pH. The salt form can be an acid or base, depending
1627 on structure; thus, its conjugate form is a base or acid, respectively.
1628 Example 1:
1629 B and BH+ represent a nonionized or “free” base and cationic acid pair, BH+ ↔ B+H+
1630 Example 2:
1631 HA and A− represent a nonionized or “free” acid and anionic base pair, HA ↔ A− + H+
1632 Example 3:
1633 HnA− and Hn−1A2−, such as H2PO4− and HPO42−, represent an anionic acid and anionic
1634 base relative to each other; the pKa = 7.2 for H2PO4− ↔ HPO42− + H+.
1635 15.1.1 CALCULATING pH
1636 Example—pH
1637 A solution contains 0.020 mol/L of sodium acetate and 0.010 mol/L of acetic acid,
1638 which has a pKa value of 4.76. Calculate the pH and the [H+] of the solution as follows:
1639 pH = 4.76 + log (0.020/0.010) = 5.06
1640 [H+] = antilogarithm of (−5.06) = 8.69 × 10−6
1641 15.2 Buffer Solutions
1642 15.2.1 DEFINITION
1643 A buffer solution is an aqueous solution that resists a change in pH when small
1644 quantities of acid or base are added, when diluted with the solvent, or when the
1645 temperature changes. Most buffer solutions are mixtures of a weak acid and one of its
1646 salts, or mixtures of a weak base and one of its salts. Water and solutions of a neutral
1647 salt, such as sodium chloride, have very little ability to resist the change of pH and are
1648 not capable of effective buffer action.
1649 15.2.2 PREPARATION, USE, AND STORAGE OF BUFFER SOLUTIONS
1650 Buffer solutions for Pharmacopeial tests should be prepared using freshly boiled and
1651 cooled water (see Reagents, Indicators and Solutions). They should be stored in
1652 containers such as Type I glass bottles and used within 3 months of preparation.
1653 Buffers used in physiological systems are carefully chosen so as to not interfere with
1654 the pharmacological activity of the medicament or the normal function of the organism.
1655 Commonly used buffers in parenteral products, for example, include: the nonionized
1656 acid and base salt pairs of acetic acid and sodium acetate, citric acid and sodium
1657 citrate, glutamic acid and sodium glutamate, and monopotassium or monosodium
1658 phosphate and dipotassium or disodium phosphate; and the acid salt and nonionized
1659 base pair tris(hydroxymethyl)aminomethane hydrochloride and
1660 tris(hydroxymethyl)aminomethane. Buffer solutions should be freshly prepared.
1661 The Henderson–Hasselbalch equation, noted in 15.1 pH Calculations, allows
1662 calculation of the pH and concentrations of conjugate pairs of weak acids and their salts
1663 and weak bases and their salts in buffer solutions when the pKa of the acid form of the
1664 buffer pair is known. Appropriately modified, this equation may be applied to buffer
1665 solutions composed of a weak base and its salt.
1666 15.2.3 BUFFER CAPACITY
1667 The buffer capacity of a solution is the measurement of the ability of that solution to
1668 resist a change in pH upon addition of small quantities of a strong acid or base. An
1669 aqueous solution has a buffer capacity of 1 when 1 L of the buffer solution requires 1 g
1670 equivalent of strong acid or base to change the pH by 1 unit. Therefore, the smaller the
1671 pH change upon the addition of a specified amount of acid or base, the greater the
1672 buffer capacity of the buffer solution. Usually, in analysis, much smaller volumes of
1673 buffer are used to determine the buffer capacity. An approximate formula for calculating
1674 the buffer capacity is g equivalents of strong acid or base added per L of buffer solution
1675 per unit of pH change, i.e., (g equivalents/L)/(pH change).
1676 15.2.4 CALCULATING BUFFER CAPACITY
1677 Example—Buffer capacity
1678 The addition of 0.01 g equivalents of sodium hydroxide to 0.25 L of a buffer solution
1679 produced a pH change of 0.50. The buffer capacity of the buffer solution is calculated as
1680 follows:
1681 (0.01 Eq/0.25 L)/0.50 pH change = 0.08(Eq/L)/(pH change)
1682
1683 16. TEMPERATURE
1684 The relationship between Celsius or Centigrade (°C) and Fahrenheit (°F) temperature
1685 scale is expressed by the following equations:
1686 °C = (°F − 32) × (5/9)
1687 °F = (°C × 1.8) + 32
1688 16.1 USP Temperatures
1689 According to the General Notices and Requirements 8.180, Temperatures,
1690 temperatures are expressed in centigrade (Celsius) degrees, and all other
1691 measurements are made at 25° unless otherwise indicated. For instructional purposes,
1692 °F is shown in the examples.
1693 16.1.1 CALCULATING TEMPERATURES
1694 Examples—Temperatures
1695 1. Convert 77°F to Celsius degrees.
1696 °C = (77°F − 32) × (5/9) = 25°C
1697 2. Convert 30°C to Fahrenheit degrees.
1698 °F = (30°C × 1.8) + 32 = 86°F
1699 The relationship between the Kelvin or absolute (K) and the Celsius (°C) scales is
1700 expressed by the equation:
1701 K = °C + 273.1
1702
1703 17. ENDOTOXINS
1704 An endotoxin is a lipopolysaccharide that comes from a particular source, where
1705 species and strain number are usually indicated.
1706 17.1 Endotoxin Concentrations
1707 For more information concerning endotoxins, see Bacterial Endotoxins Test 85 .
1708 17.1.1 CALCULATING ENDOTOXINS
1709 Example—Endotoxins
1710 A 71.8-kg patient is to receive an intrathecal infusion of morphine sulfate at a rate of
1711 0.3 mg/hour. The solution will be prepared by diluting preservative-free morphine sulfate
1712 injection, which contains 10 mg/mL of morphine sulfate, with 0.9% sodium chloride
1713 injection to produce an infusion rate of 2 mL/h.
1714 1. Determine the volume, in mL, of morphine sulfate injection (10 mg/mL) and 0.9%
1715 sodium chloride injection needed to prepare a 24-hour infusion.

1716 0.3 mg of morphine sulfate/hour × 24 hours = 7.2 mg of morphine sulfate

1717 7.2 mg of morphine sulfate/(10 mg/mL) = 0.72 mL of morphine sulfate injection

1718 2 mL of infusion/h × 24 h = 48 mL of total volume

1719 48 mL total volume − 0.72 mL morphine sulfate injection = 47.28 mL of 0.9%

1720 sodium chloride injection

1721 2. Calculate the maximum potential endotoxin load/hour for this preparation. [NOTE—
1722 USP monographs specify upper limits of 14.29 USP Endotoxin Units (EU)/mg of
1723 morphine sulfate in injections for intrathecal use, and 0.5 EU/mL for injections
1724 containing 0.5%–0.9% sodium chloride.]

1725 7.2 mg of morphine sulfate injection × 14.29 EU/mg of morphine sulfate =

1726 102.89 EU from morphine sulfate

1727 47.28 mL of sodium chloride injection × 0.5 EU/mL = 23.64 EU from 0.9%
1728 sodium chloride injection

1729 Endotoxin load = 102.89 EU + 23.64 EU = 126.53 EU

1730 126.53 EU/24 hour = 5.27 EU/hour

1731 3. Determine if the endotoxin load in step 2 exceeds the allowable USP limit for this
1732 patient. [NOTE—The maximum endotoxin load by intrathecal administration is 0.2
1733 EU/kg/hour (see chapter 85 ).]

1734 Maximum endotoxin load = (0.2 EU/kg/hour) × 71.8 kg-patient = 14.36 EU/hour

1735 The endotoxin load of 5.27 EU/hour does not exceed the allowable limit of
1736 14.36 EU/hour.

1737
1738 18. STABILITY AND EXPIRATION DATE CALCULATIONS
1739 18.1 Stability Based on Rate Calculations
1740 Calculation of a predetermined minimum percentage of initial drug strength or other
1741 quality parameter, e.g., in vitro dissolution of active pharmaceutical ingredients (APIs) or
1742 active drugs in solid oral dosage forms, is based on component-specific assays and
1743 other validated scientific testing. The expiration date or time elapsed until such minimum
1744 acceptable limits are reached for a specific manufactured product is exclusive to the
1745 specific formulation, packaging, and environmental conditions, e.g., temperature,
1746 humidity, and illumination, to which the item is subjected. See also chapters 659 ,
1747 795 , 797 , 1163 , and 1191 .
1748 The degradation or concentration loss rates or kinetics of most APIs can be accurately
1749 represented or modeled by either zero order (constant) or first order (mono-exponential)
1750 rate equations. Zero order calculations are generally applicable to solids, semisolids,
1751 suspensions in which a majority of the drug strength is present as solid particles, and
1752 auto-oxidation in solutions. First order calculations are generally applicable for drug
1753 hydrolysis in solutions.
1754 18.2 Zero Order Rate Calculations
1755 The isothermal zero order or constant rate equation for a particular formulation is C =
1756 C0 − kt, where C is the concentration of API at any time, C0 is the concentration at
1757 origination or time zero, k is the reaction rate constant, and t is any time after origination
1758 or zero. The values and units of the rate, dC/dt, and rate constant, k, are the same for
1759 zero order processes, i.e., the units are concentration/time, such as mg/mL/day.
1760 18.2.1 ZERO ORDER RATE EQUATION DERIVED FROM ORIGINAL DATA
1761 The following examples illustrate calculations of the zero order rate equation from
1762 original concentration assay and time data, and an expiration date using that equation.
1763 18.2.1.1 Calculating zero order rate:
1764 Examples—Zero order rate
1765 1. Calculate the zero order rate equation based on the assay results for a drug
1766 suspension at 25° (see Table 6):
1767 Table 6

C (mg/mL) t (days)
49 3
47.5 8
44.8 17
42.3 26
1768 Linear regression of the C (ordinate) versus t (abscissa) values yields the equation, C
1769 = 49.84 − 0.292t with a correlation coefficient of −0.9998.
1770 2. Calculate the time when C = 0.9 × C0, i.e., the expiration date where the
1771 concentration will be 90% of the original concentration (t90):
1772 C = 49.84 − 0.292t
1773 0.9 × 49.84 = 49.84 − 0.292(t90)
1774 t90 = (44.86 − 49.84)/−0.292 = 17.05 days
1775 3. Using the previous linear regression equation, calculate the C of the drug
1776 suspension at 25° when t = 12 days:
1777 C = 49.84 − (0.292 × 12) = 43.34 mg/mL
1778 4. Calculate t when C = 45 mg/mL:
1779 45 = 49.84 − 0.292t
1780 t = (45 − 49.84)/−0.292 = 16.6 days
1781 18.2.2 ZERO ORDER VALUES CALCULATED FROM A RATE EQUATION
1782 The following are examples of expiration dates calculated from a rate equation derived
1783 from original concentration assay and time data.
1784 18.2.2.1 Calculating zero order values from a rate equation:
1785 Examples—Zero order from a rate equation
1786 1. Calculate the t80 expiration date of a drug cream at 25° using the equation, C = 0.05
1787 − 0.0003t, where the C unit is % w/w and the t unit is months. At t80, C = 0.8C0.
1788 0.8 × 0.05 = 0.05 − 0.0003(t80)
1789 t80 = 33.3 months
1790 2. Calculate the t80 expiration date of the drug cream formulation in example 1, but for
1791 which C0 is 0.1:
1792 0.8 × 0.1 = 0.1 − 0.0003(t80)
1793 t80 = 66.7 months
1794 18.3 First Order Rate Calculations
1795 The isothermal first order rate equation for a particular formulation in exponential form
1796 is C = C0e , and in linear form is ln(C) = ln(C0)−kt, where C is the concentration of an
−kt

1797 API at any time, C0 is the concentration at origination or time zero, k is the reaction rate
1798 constant, and t is any time after origination or zero. The constantly changing rate, dC/dt,
1799 and rate constant, k, are not the same for first order processes. The rate units are
1800 concentration/time, e.g., mg/mL/hour, but the rate constant unit is reciprocal time, time−1,
1801 e.g., hour−1.
1802 18.3.1 FIRST ORDER LINEAR RATE EQUATION DERIVED FROM ORIGINAL DATA
1803 The following examples illustrate calculation of the linear first order rate equation from
1804 original concentration assay and time data and calculation of an expiration date using
1805 that equation.
1806 18.3.1.1 Calculating first order linear rate equations:
1807 Example—First order linear rate
1808 1. Calculate the linear first order rate equation based on the assay results for a drug
1809 solution at 27° (see Table 7):
1810 Table 7

C (mg/mL) t (hour)
12.3 2
11.9 6
11.5 14
10.6 24
1811 Linear regression of the ln(C) (ordinate) versus t (abscissa) values yields the equation,
1812 ln(C) = 2.522 − 0.0065t with a correlation coefficient of 0.992.
1813 2. From the linear regression equation, calculate the time when 95% of the original
1814 concentration is reached, t95, when C = 0.95C0, which is the predetermined expiration
1815 date:
1816 ln(C0) = 2.522; thus, C0 = e2.522 = 12.45 mg/mL
1817 ln(0.95 × 12.45) = 2.522 A 0.0065(t95)
1818 t95 = (2.470 − 2.522)/−0.0065 = 8 hours
1819 18.3.2 FIRST ORDER VALUES CALCULATED FROM A LINEAR EQUATION
1820 The following are examples of an expiration date, concentration, and time calculated
1821 for the same drug solution at 22° from the rate equation, ln(C) = 4.382 − 0.076t, where
1822 the C units are µg/mL and the t unit is days, derived from the original concentration
1823 assay and time data.
1824 18.3.2.1 Calculating first order values from a linear rate equation:
1825 Examples—First order from a linear rate
1826 1. Calculate the t90 expiration date:
1827 ln(C0) = 4.382; thus, C0 = e4.382 = 80
1828 ln(0.9 × 80) = 4.382 − 0.076(t90)
1829 t90 = (4.277 − 4.382)/−0.076 = 1.4 days
1830 2. Calculate the time at which C = 75 µg/mL:
1831 ln(75) = 4.382 − 0.076t
1832 t = (4.317 − 4.382)/−0.076 = 0.86 day
1833 3. Calculate whether C = 70 µg/mL occurs before or after t90:
1834 ln(70) = 4.382 − 0.076t
1835 t = (4.248 − 4.382)/−0.076 = 1.8 days
1836 C = 70 µg/mL occurs at 1.8 days, after a t90 of 1.4 days
1837 18.3.3 FIRST ORDER EXPIRATION DATE CALCULATED FROM TWO VALUES OF CONCENTRATION
1838 AND TIME
1839 When degradation or other cause of concentration loss is known from experience or
1840 reference information to obey first order kinetics, the rate constant can be accurately
1841 estimated from accurate assays of only two concentrations at their respective times. In
1842 this case, the linear first order rate equation, ln(C) = ln(C0) − kt, may be transformed or
1843 integrated as ln(C2) = ln(C1) − k(t2 − t1), which when rearranged is k = ln(C1/C2)/(t2 − t1).
1844 The following examples apply these equations to calculate expiration dates,
1845 concentrations, and times.
1846 18.3.3.1 Calculating first order expiration date from two values:
1847 Examples—First order expiration date from two values
1848 1. At 25°, the concentration of an antibiotic in solution was 89 mg/mL after 3 hours and
1849 74 mg/mL after 8 hours. Calculate the initial concentration at time zero:
1850 k = ln(89/74)/(8 − 3) = 0.037 hour−1
1851 ln(89) = ln(C0) − (0.037 hour−1 × 3 hour)
1852 ln(C0) = 4.489 + 0.111 = 4.6
1853 C0 = e4.6 = 99.5 mg/mL
1854 2. Calculate the t90 expiration date using the data in example 1. At t90, C = 0.9C0.
1855 ln(0.9 × 99.5) = ln(99.5) − 0.037(t90)
1856 t90 = (4.495 − 4.600)/−0.037 hour−1 = 2.8 hour
1857 3. Calculate the concentration at 6 hour using the data in example 1:
1858 ln(C) = ln(99.5) − (0.037 × 6)
1859 ln(C) = 4.378
1860 C = e4.378 = 79.7 mg/mL
1861 18.3.4 FIRST ORDER TIMES, TN, FOR 0.N FRACTION OR N% OF REMAINING ORIGINAL
1862 CONCENTRATION
1863 The two most common first order pharmaceutical tn values are the t50, which is a
1864 primary parameter factor in clinical pharmacokinetics, and the t90, which is the most
1865 common stability shelf life or expiration date. Values of any tn, where 0 < n < 100, are
1866 derived from the linear first order equation, ln(C) = ln(C0) − kt. The equations for t50 and
1867 t90 in particular are derived in the following examples. The value of k by definition is
1868 constant for a specific drug chemical in a specific formulation at a specific temperature;
1869 thus, tn values derived from such values of k are also constant.
1870 18.3.4.1 Calculating first order times for remaining original concentrations:
1871 Examples—First order times for remaining original concentrations
1872 1. At tn, C = 0.n × C0.
1873 ln(0.n × C0) = ln(C0) − ktn
1874 tn = [ln(0.n × C0) − ln(C0)]/−k = ln[(0.n × C0)/C0]/−k = ln(0.n)/−k
1875 tn = ln(0.n)/−k
1876 2. At t50, C = 0.5(C0).
1877 ln(0.5 × C0) = ln(C0) − kt50
1878 t50 = [ln(0.5 × C0) − ln(C0)]/−k = ln[(0.5 × C0)/C0]/−k = ln(0.5)/−k = −0.693/−k = 0.693/k
1879 t50 = 0.693/k
1880 3. At t90, C = 0.9(C0).
1881 ln(0.9 × C0) = ln(C0) − kt90
1882 t90 = [ln(0.9 × C0) − ln(C0)]/−k = ln[(0.9 × C0)/C0]/−k = ln(0.9)/−k = −0.105/−k = 0.105/k
1883 t90 = 0.105/k
1884 18.4 Stability Prediction Based on Arrhenius Theory
1885 The basis of the Arrhenius theory is that reaction rates and rate constants change
1886 exponentially in the direction of arithmetic temperature change. The pharmaceutical
1887 application of the Arrhenius theory is based on scientifically accurate and statistically
1888 valid assay data obtained at three or more temperatures that are ≥10° warmer than the
1889 intended drug storage temperature and each other. The Arrhenius equation may be
1890 expressed in an exponential form, k = Ae−( / ), a linear form, ln(k) = ln(A) − (Ea/RT), and
Ea RT

1891 an integrated form, ln(k2/k1) = Ea(T2 − T1)/[R(T2 × T1)], where k, k1, and k2 are isothermal
1892 rate constants, A is a thermodynamic factor, Ea is energy of activation for the
1893 degradation reaction, R is the gas constant (1.987 × 10−3 kcal mol−1K −1 or 8.314 × 10−3 J
1894 K−1 mol−1), and T, T1, and T2 are absolute or Kelvin temperatures.
1895 18.4.1 ARRHENIUS LINEAR EQUATION DERIVED FROM ORIGINAL DATA
1896 The following examples illustrate derivation of a linear Arrhenius equation from original
1897 assay data and its application to predicting a drug stability expiration date at a cooler or
1898 lower storage temperature.
1899 18.4.1.1 Calculating Arrhenius equations:
1900 Examples—Arrhenius equations
1901 1. Calculate the linear Arrhenius equation based on the rate constants and
1902 temperatures for a beta-lactam antibiotic that decomposes in solution at a first order
1903 rate (see Table 8):
1904 Table 8

T (°C) T (K) 1/T (K−1) k (hour−1) ln(k)

40 313 3.195 × 10−3 0.0014 −6.571
50 323 3.096 × 10−3 0.005 −5.298
60 333 3.003 × 10−3 0.016 −4.135
1905 Linear regression of the ln(k) (ordinate) versus 1/T (abscissa) values yields the
1906 equation, ln(k) = 33.977 − (12,689/T) with a correlation coefficient of 0.99997.
1907 2. Calculate the t90 shelf life expiration date, in days, at 25°C (298 K) using the equation
1908 in example 1:
1909 ln(k25) = 33.977 − (12,689/298) = 33.977 − 42.581 = −8.604
1910 k25 = e−8.604 = 1.834 × 10−4 hour−1 = 4.402 × 10−3 day−1
1911 t90 = 0.105/k = 0.105/4.402 × 10−3 day−1 = 23.85 days
1912 t90 at 25°C = 23.85 days
1913 18.4.2 STABILITY PREDICTIONS USING THE INTEGRATED ARRHENIUS EQUATION
1914 The following examples illustrate stability predictions based on one accurately
1915 determined isothermal rate constant and adherence to the same degradation rate order,
1916 e.g., first order, at temperatures at which stability is to be calculated from the equation,
1917 ln(k2/k1) = Ea(T2 − T1)/[R(T2 × T1)].
1918 18.4.2.1 Calculating stability prediction using integrated Arrhenius equation:
1919 Example—Stability using integrated Arrhenius equations
1920 1. Calculate the t85 stability expiration date at 4°C (277 K) for an ester hydrolysis with
1921 an Ea = 15 kcal/mol and k = 0.0045 hour−1 at 23°C (296 K):
1922 ln(k277/0.0045) = 15(277 − 296)/[1.987 × 10−3 (277 × 296)]
1923 ln(k277) − ln(0.0045) = −285/162.92
1924 ln(k277) = −1.749 + ln(0.0045) = −7.153
1925 k277 = e−7.153 = 7.825 × 10−4 hour−1
1926 t85 = ln(0.850)/k277 = −0.163/−7.825 × 10−4 hour−1 = 208.3 hours
1927 t85 at 4°C = 208.3 hours (t85 at 23°C is 36.2 hours)
1928 18.4.3 ARRHENIUS-BASED Q10 STABILITY ESTIMATION
1929 The temperature coefficient (Q10) represents the multiplicative factor by which a
1930 chemical reaction rate constant changes in the same direction as the temperature for
1931 each 10°C change. For drug molecules, Q10 ranges from 2 to 5, corresponding to an Ea
1932 range of 10–25 kcal/mol or 42–105 kJ/mol. A Q10 of 3 yields reasonable estimates of
1933 drug stability in the equation, (tn at T2) = (tn at T1)/{Q10 }, where n is a percentage of
1934 remaining C0, T1 is the temperature at which tn is known, and T2 is the temperature at
1935 which tn is to be estimated. Calculations using Q10 values of both 2 and 4 may be used to
1936 obtain the shortest or most conservative stability estimate, but Q10 = 3 is applied in the
1937 following two example.
1938 18.4.3.1 Calculating Arrhenius-based Q10 stability estimation:
1939 Example—Arrhenius-based Q10 stability
1940 1. Estimate the t90 expiration date in hours of an antibiotic suspension stored in a
1941 closed automobile at 57° for which the 8° refrigeration t90 is 14 days.
1942 t90 at 57° = [14 days × (24 hours/day)]/{3[(57 − 8)/10]} = 336 hours/34.9 = 336 hours/217.7 = 1.54
1943 hours
1944 t90 at 57° = 1.54 hours
1945
1946 APPENDIX 1: LOGARITHMS
1947 The logarithm of a number is the exponent or power to which a given base number
1948 must be raised to equal that number. Thus, the logarithm of Y to the base, b, equals X,
1949 or logb(Y) = X. The logarithm of 0 and all negative numbers is undefined or nonexistent.
1950 The logarithm of 1 is 0 and of numbers <1 is negative in all systems (see Table 9).
1951 Table 9. Common (or Briggsian) and Natural (or Napierian) Logarithms

Antilogarithm
Logarithmic Abbreviation or Base or Inverse
System Symbol Number Format Logarithm
Common Log 10 log Y = X 10 = Y X

Natural Ln e or 2.7183a ln Y = X e =Y
X

e is an irrational number derived from an infinite series of reciprocal whole number factorials, e = 1 +
a 

1/1! + 1/2! + 1/3! + 1/4! ... + 1/n!, where n = infinity. e rounds to 2.7183 when n ≥ 8.
1952 2. The relationships between common and natural logarithms are the following:

1953 a. log Y = ln Y/ln 10 = ln Y/2.303

1954 b. ln Y = ln 10 × log Y = 2.303 × log Y
1955 3. Rules for some common calculations with logarithms are shown in Table 10.
1956 Table 10. Rules for Calculating with Logarithms

Formula Example
ln(0.62) + ln(1.73) = ln(0.62 × 1.73) =
ln(A) + ln(B) = ln(A × B) ln(1.0726) = 0.070
Additions and log(A) + log(B) = log(A × log(5.7) + log(0.43) = log (5.7 × 0.43) =
multiplications B) log(2.451) = 0.389
ln(0.5) − ln(4) = ln(0.5/4) = ln(0.125) =
ln(A) − ln(B) = ln(A/B) −2.079
Subtraction and log(A) − log(B) = log(1.57) − log(2.48) = log(1.57/2.48) =
quotients log(A/B) log(0.6330645) = −0.199
13.6 = 1.25
−Z

ln(1.25) = −Z × ln(13.6)
Z = −ln(1.25)/ln(13.6) = −0.223/2.610 =
−0.085
0.57 = 2.3
Z

log(2.3) = Z × log(0.57)
Simple non-base ln(Y ) = Z × ln(Y)
z
Z = log(2.3)/log(0.57) = 0.362/−0.244 =
exponentials log(Y ) = Z × log(Y)
z
−1.484
In (a × e ) = ln(x) ↔
±b

ln(a) ± b = ln(x) 67 × 10 = 15.1

b

log(67) + b = log(15.1)
log (a × 10± ) = log(x) ↔ 1.826 + b = 1.179
b

Base exponentials log(a) ± b = log(x) b = 1.179 − 1.826 = −0.647▪1S (USP38)

1957