(qaPTEn 8: BUFFERED AND ISOTONIC SOLUTIONS werH00S pe ADJUSTING TONICITY AND pH ah pe of several methods can be used to calculate the quantity, CFeodium chloride, dextrose, and other substances that may fe added to solutions of drugs to render them isotonic. Fordiscussion purposes, the methods are divided into two cusses. Inthe class Imethods, sodium chloride or some other Sobstance is added to the solution of the drug to lower the frezing point of the solution to ~0.52°C and thus make jt isotonic with body fluids. Under this class are included the eryoscopic method and the sodium chloride equivalent ‘pethod. Inthe class II methods, water is added to the drug in {sufficient amount to form an isotonic solution. The prepa- ‘ation is then brought to its final volume with an isotonic or a tutfered isotonic dilution solution, Included in this class are the White-Vincent method and the Sprowls method. Class | Methods Gryoscopic Method ‘The freezing point depressions of a number of drug solu- tions, determined experimentally or theoretically, are given in Table 9-4. According to the previous section, the freezing point depressions of drug solutions that have not been de- ‘ernmined experimentally can be estimated from theoretical considerations, knowing only the molecular weight of the drug and the Liso value of the ionic class. ‘The calculations involved in the cryoscopie method are explained best by an example. we Tbotomicity How much sodium chloride i required to render 100 mL. of a 1% solution of apomorphine hy isotonic with blood serum? From Table 9-4 it is found that a 1% solution of the drug has a {teezing point lowering of 0.08°C. Tomakethissolutionisotonicwith ‘ood, suficient sodium chloride must be added to reduce the free2- ‘ng point by an additional 0.44°C (0.52°C — 0.08°C). Inthe freezing point table, it is also observed that a 1% solution of sodium chloride hasa freezing point lowering of0.58°C. By the method of proportion, 1% _ 0.58" x 04a ‘Thus, 0.76% sodium chloride will lower the freezing point the required 044°C and will render the solution isotonic. The solution. 's prepared by dissolving 1.0 g of apomorphine hydrochloride and 0.76 g of sodium chloride in sufficient water to make 100 mL. of solution, 76% Sodium Chloride Equivalent Method A second method for adjusting the tonicity of pharmaceutical solutions was developed by Mellen and Seltzer.*® The sodium chloride equivalent or, as referred to by these workers, the “tonicic equivalent” of a drug is the amount of sodium chlo- ride that is equivalent to (ie. has the same osmotic effect as) 1g, or other weight unit, of the drug. The sodium chloride equivalents E for a number of drugs are listed in Table 9-4. 223 When the £ value for a new drug is desired for inclusion in Table 9-4, itcan be calculated from the Lise value or freezing point depression ofthe drug according to formulas derived by Goyan et al For a solution containing 1 g of drug in 1000 ml of solution, the concentration c expressed in moles/liter can be written as 1g Molecularweight a) and from equation (9-36) 2 lg AT; = Liege Now, E's the weight of NaCl with the same freezing point de- pression as | g ofthe drug, and for a NaCI solution containing E grams of drug per 1000 mL, E Seas where 3.4 is the Lisp value for sodium chloride and 58.45, is its molecular weight. Equating these two values of AT; yields AT, (9-43) (9-44) (9-45) Calculate the approximate E value for a new amphetamine hy- Arochloride derivative (molecular weight 187). ‘Because this drug isa uni-univalent salt, it has an Ly value of 34. Its E values calculated from equation (9-45): Calculations for determining the amount of sodium chlo- ride or other inert substance to render a solution isotonic (across an ideal membrane) simply involve multiplying the quantity of each drug in the prescription by its sodium chlo- ride equivalent and subtracting this value from the concen- tration of sodium chloride that is isotonic with body fluids, namely, 0.9 g/100 mL. BOE ‘Tonicity Adjustment ‘A solution contains 1.0 g of ephedrine sulfate in a volume of 100 mL. What quantity of sodium chloride must be added to make the solution isotonic? How much dextrose would be required for this purpose? ‘The quantity of the drug is multiplied by its sodium chloride equivalent, E, giving the weight of sodium chloride to which the ‘quantity of drug is equtvalent in osmotic pressure: Ephedrine sulfate: 1.0g x 0.23 = 0.238,SECTION 2: EQUILIBRIUM PHENOME, ‘Substance MW Eg vo ary* / ‘Alcohol, dehydrated 4607 070 73 oat a “Amigophyline 456.46 017 57 010 a ‘Ammonium chloride 5350 1.08 %6 0.64 u ‘Amphetamine sulfate 36849 02 73 O13 7, (benzedrine sulfate) Aatpyrine 188.22 017 s1 010 5 ig Antistine hydrochloride x0181 ous 60 ou 2 (antazoline hydrochloride) 4 ‘Apomorphine hydrochloride 31279 01s 47 008 as Ascorbie acid 176.12 ois 60 on D Atropine sulfate 492 01 3 007 33 “Aureomycin hydrochloride sas on a7 006 3 ‘arbi sodium 206.18 029 100 02 33 Benady| hydrochloride 2181 020 66 038 34 (diphenhydramine hydrochloride) Boric acid 6184 050 167 029 u Butacaine sulfate 03s 020 67 on a (uty slate) caffeine 194.9 008 27 005 0 Caffeine and sodium benzoate = 025 a7 028 = Calcium chloride 2140 703 031 179 030 a Calcium slaconate 448.39 016 53 0.09 a Cater atte 308.30 023 7 ou a Camphor 15223 020 67 or a CGoramphenicol (chloromycati) mal 010 33 005 3 CCorotutanl(choretone) a7 024 80 ou as Cocaine hydrochloride 23081 01 53 00 32 ‘Cupric sulfate - SH;O 249.69 0.18 60 OL 26 Dentro HO 198.17 016 53 00 9 Dice hydrochloride 379.92 013 a 0.08 2» (nupercaine hydrochloride) Enetne hydrochloride 553.56 10 33 006 33 Ephedrine hydrochloride 201.69 0.30 10.0 O18 36 Ephedrine slfite 22854 023 17 ou ss Epinephrine bitarrate 33329 ous 60 on 35 Bpineptrine hydrochloride 219.66 029 97 on 37 Ethylhydrocupreine hydrochloride ‘316.92 017 57 0.10 38 (optochin) Ehylmorphie hydrochloride (conin esse os 33 009 36 catopine hydrochloride aries O18 60 oul 35 (cuphthaline hydrochloride) Fhiorecein sodium m6 031 103 ors “6 Glycerin 92.09 034 u3 020 u ‘Homatropine hydrobromide 356.26 0.17 ST 0.10 36 Lactove 36031 007 23 0.04 u Magnesium sulfate 71:0 246.50 017 57 010 as Menthol 156.26 0.20 67 0.12 Be ‘Meperidine hydrochloride 283.79 0.22 73 0.12 at (demerol hydrochloride) Mercurie chloride ms 013 43 00s a (rercury bichorde) Mereric cyanide 25265 ous 50 0 22 Mercuric succinimide 396.77 0.14 48 0.08 33 (contimeed)wAPTER 9: BUFFERED AND IsoToMC so.uTions substance ine chloride (cecholyl chloride) ‘ etamphetamine hydrochloride 185.69 037 23 on 40 (desoxyepherine hydrochloride) Meiyesin hydrochloride 292.82 020 67 on 34 ‘Mid iver protein = 0.18 60 on = Morphine hydrochloride 37584 os 50 0.09 33 Morphine sulfate 758382 os 43 0.08 62 Naphazoline hydrochloride 246.73 o27 17 016 33 ‘Gavine hydrochloride) Neomycin sulfate = ont 37 0.05 a eostgmine bromide 303.20 on 60 out 32 (prstigmine bromide) Nicotinamide 1213 026 87 ous 19 FesicilinG potassiam snr 018 60 on 39 Pesicilin G Procsine saa 0.10 33 0.06 33 Feelin G sodium 355.38 018 60 ont 38 Phenacaine hydrochloride 352.85 020 53 oun 33 (holocsine hydrochioride) Paenobarbital sodium 25422 024 80 os 36 Phenol 94.1 035 na 020 19 Phenylephrine hydrochloride 203.67 032 97 0.18 33 (aeosynephrine hydrochloride) Paysostgmine salicylate 41346 016 53 0.09 39 Physostigmine sulfate 648.45 013 3 0.08, 50 Pocarpine nitrate mat 023 1m 018 37 Potassium acid phosphate 13613 043 142 025 34 (Kii,PO.) Potassium chloride 143s 076 253 04s 33 Possum iodide 166.02 034 13 020 33 Procane hydrochloride mn 021 70 012 3a Quinine hydrochloride 39691 014 47 0.08 33 Quinine and urea hydrochloride 54748 023 7 ons 74 Scopolamine hydrobromide 438.32 012 40 oo7 31 (byoscine hydrobromide) Silver nitrate 169.89 033, 110 ous 33 Sodium acid phosphate 138.00 040 B3 024 32 (NaHPO. #0) Sodium benzoate want 040 B3 024 34 Sodium bicarbonate #400 oss 217 038, 32 Sodium bisulfite 10407 ost 203 036 37 Sodium borate + 1080 381.43 042 140 025 94 Sodium chloride sas 1.00 333 058 34 Sou iodide 149.92 039 30 023, 34 Sodium nitrate 8501 068 27 039 3a Sodium phosphate, anhydrous M4198 053 117 031 44 Sodium phosphate »2H,0 17805 042 40 os 4a Sodium phosphate - 7H,0 268.08 029 97 017 46 Sodium phosphate - 12,0 35821 o22 3 013 46 Sodium propionate 9607 061 203, 036 34 Sodium sulfite, exsiceated 126.06 065 217 038, 4s Streptomycin sulfate 1457.44 0.07 23 0.04 60 Song silver protein = 0.08 27 0s = Sucrose 34230 0.08 27 00s 16 Sulfcetamide sodium 25425 023, 7 0.14 34