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Figure 69 Simulated Bjerrum plots of saturated solutions of an acid, a base, and an ampholyte The sample concentration was chosen as 2 M, a special condition where the difference between the true pKa and the apparent pKa is equal to log S0 [Avdeef, A, Curr Topics Med Chem, 1, 277 351 (2001) Reproduced with permission from Bentham Science Publishers, Ltd]
EXPERIMENTAL METHODS
using as little sample as necessary to cause precipitation near the mid-point For compounds extremely insoluble in water, cosolvents such as methanol, ethanol, DMSO, or acetonitrile may be used, with the solubility constant determined by extrapolation to zero cosolvent [43] Usually, the solubility of the salt is determined from separate, more concentrated solutions To conserve on sample, the titration of the salt may be performed with an excess of the counterion concentration [479] Also, some amount of sample salt may be conserved by titrating in cosolvent mixtures, where salts are often less soluble The graphically deduced constants are subsequently re ned by a weighted nonlinear least squares procedure [472] Although the potentiometric method can be used in discovery settings to calibrate high-throughput solubility methods and computational procedures, it is too slow for HTS applications It is more at home in a preformulation lab 645 Fast UV Plate Spectrophotometer Method
A high-throughput method using a 96-well microtiter plate format and plate UV spectrophotometry has been described [26] Solubilities at a single pH, or at 12 pH values can be determined, using one of two methods 6451 Aqueous Dilution Method A known quantity of sample is added to a known volume of a universal buffer solution of suf cient capacity and of known pH The amount of sample must be suf cient to cause precipitation to occur in the formed saturated solution After waiting for a period of time to allow the saturated solution to reach the desired steady state, the solution is ltered to remove the solid and obtain a clear solution, whose spectrum is then taken by the UV spectrophotometer Mathematical treatment of the spectral data yields the area-under-the-curve of the ltered sample solution, AUCS A reference solution is prepared by a dilution method A known quantity of sample is dissolved in a known volume of the system buffer of known pH; the amount of sample is X times less than in the above case in order to avoid precipitation in the formed solution The spectrum is immediately taken by the UV spectrophotometer, to take advantage of the possibility that solution may be supersaturated (ie, solid should have precipitated, but because not enough time was allowed for the solid to precipitate, the solution was temporarily clear and free of solid) Mathematical treatment of the spectral data yields the AUC of the reference sample solution, AUCR The ratio R AUCR =AUCS is used to automatically recognize the right conditions for solubility determination: when the reference has no precipitate, and the sample solution is saturated with precipitate Under these conditions, solubility is determined from the expression S CR R 6:16
SOLUBILITY
TABLE 61 Intrinsic Solubility S0, Corrected for the Drug DMSO/Drug Aggregation Effects Compound Amitriptyline Chlorpromazine Diclofenac Furosemide Griseofulvin Indomethacin Miconazole 2-Naphthoic acid Phenazopyridine Piroxicam Probenecid Terfenadine
pKa 945a 924a 399b 1063, 352b Nonionizable 442a 607f 416f 515f 507, 233h 301f 953f
SAPP 0 (mg/mL) 569 194 226 298 376 72 111 333 122 105 46 44
Corrected S0 (mg/mL) 30 34 38 29 202 41 16 202 122 11 07 01
pSOL Shake-Flask S0 (mg/mL) S0 (mg/mL) 20a 35a 08b 59b 20a 07f 143f 06f 01f 20a 01a 06b 120b (29c ) 9d 20a , 1e 224g 91i (33c ), 8 16j (22 44c )
M A Strafford, A Avdeef, P Artursson, C A S Johansson, K Luthman, C R Brownell, and R Lyon, Am Assoc Pharm Sci Ann Mtng 2000, poster presentation b Ref 433 c Corrected for aggregate formation: unpublished data d J Huskonen, M Salo, and J Taskinen, J Chem Int Comp Soc 38, 450 456 (1998) e Ref 507 f pION, unpublished data g K G Mooney, M A Mintun, K J Himmestein, and V J Stella, J Pharm Sci 70, 13 22 (1981) h Ref 162 i C R Brownell, FDA, private correspondence, 2000 j Ref 500 (24 h)
where CR is the calculated concentration of the reference solution Some results are presented in Table 61 The apparent intrinsic solubilities Sapp , determined in this 0 way (eq 616) are listed in column 3, for the compounds used in one study All the Sapp values reported in Table 61 were determined in the presence of 05% v/v 0 DMSO, except for phenazopyridine, where 026% was used The results of a pH 4 95 solubility assay of chlorpromazine are shown in Fig 610 The horizontal line represents the upper limit of measurable solubility (eg, 125 mg/mL), which can be set by the instrument according to the requirements of the assay When the measured concentration reaches the line, the sample is completely dissolved, and solubility cannot be determined This is automatically determined by the instrument, based on the calculated value of R When measured points fall below the line, the concentration corresponds to the apparent solubility Sapp 6452 Cosolvent Method The sample plate is prepared as in the preceding method But before the spectra are taken, a volume Y of a water-miscible cosolvent is added to a volume Z of sample