A. POBUDKOWSKA, U. DOMAŃSKA: STUDY

A. POBUDKOWSKA, U. DOMAŃSKA: STUDY OF PH-DEPENDENT DRUGS… Chem. Ind. Chem. Eng. Q. 20 (1) 115−126 (2014)
119
pH p a
log log log(1 10 )S S= + +0 − K (1a)
and for monoprotic bases:
p a pH
log log log(1 10 )S S= + +0 K − (1b)
where S0 is the intrinsic solubility, S is the predicted
solubility at a given pH, and pKa is a pH at which the
concentration of unionized and ionized forms of a
monoprotic drug in the solution are equal. The HH
equation describes solubility as a function of pH. This
equation always predicts an increasing solubility of all
weak acids as pH increases, and descending solubility of bases when pH increases. In this paper all
solubility values, S (mol dm–3) are expressed as log S
and are calculated from the HH equation for monoprotic acids (Eq. (1a)). The intrinsic solubility, S0, was
developed from the solubility-pH profile. Using the HH
equation, the calculated curves were drawn for all
experimentally studied drugs.
RESULTS AND DISCUSSION
The pKa of an ionisable compound is an important property, describing the charge state of the drug
at a certain pH. However, according to Avdeef [6], it is
not recommended to determine pKa values from the
solubility-pH measurements (pKaS). The results listed
in Table 3 show a reasonably good agreement
between the results obtained by the two different
methods at two temperatures: from the solubility-pH
measurements (pKaS), and with the precise spectrophotometric Bates-Schwarzenbach method (pKaB-S).
The pKaS values were obtained from the crossing of
two lines interpolated from the experimental points for
the unionized and ionized form of the chosen drug.
The parameters and correlation coefficients are listed
in Table 3. All the literature data of pKa values,
obtained with different methods (including ours at
298.2 K for comparison) are presented in Table 4.
Generally, our values are higher than those from literature with the exception of MEF. In our opinion the
Bates-Schwarzenbach method is more precise
because it does not use the co-solvent and the extrapolated values to pure aqueous solutions.
The classical shake-flask method was applied to
measure the equilibrium solubility at two temperatures
for five drugs over a wide pH range from 2 to 8 or 9.
The time of stirring was chosen as 24 h at the same
temperature and pH to get the repeatable results.
After stirring, the two phases (solution and solid material) of the saturated solution were separated, and
after 6 h (the necessary time needed for the separation of two phases) the supernatant was taken out
for the concentration of drug measurements by
HPLC-UV-Vis spectrometry. The theoretical HH solubility, S, was predicted based on the pKaB-S values
and the intrinsic solubilities, S0 determined by the
shake-flask method at two temperatures. Data are
listed in Table 4 together with the literature data of S0.
The results are discussed for each drug separately.
Flufenamic acid
During the last few years there were different
values of pKa and S0 discussed in the literature at
temperature 298.2 K for FLU. Our value of pKa = 4.62
[20] is close to the presented by Muñoz et al. [27],
pKa = 4.17 and higher than all remaining data. In our
opinion, the reason may also be insufficient control of
the equilibrium temperature. The same parameters
are responsible also for the values of the intrinsic
solubility, S0. The value obtained in this work at T =
Table 3. The linear regression parameters, a1, b1 for the unionized form and a2, b2 for the ionized form, the corresponding correlation
coefficients, R1 and R2, the pKaS developed from the solubility-pH profile and the pKaB-S obtained from the Bates-Schwarzenbach method

Hasil (Bahasa Indonesia) 1:

A. POBUDKOWSKA, U. DOMAŃSKA: STUDY OF PH-DEPENDENT DRUGS… Chem. Ind. Chem. Eng. Q. 20 (1) 115−126 (2014)119pH p alog log log(1 10 )S S= + +0 − K (1a)and for monoprotic bases:p a pHlog log log(1 10 )S S= + +0 K − (1b)where S0 is the intrinsic solubility, S is the predictedsolubility at a given pH, and pKa is a pH at which theconcentration of unionized and ionized forms of amonoprotic drug in the solution are equal. The HHequation describes solubility as a function of pH. Thisequation always predicts an increasing solubility of allweak acids as pH increases, and descending solubility of bases when pH increases. In this paper allsolubility values, S (mol dm–3) are expressed as log Sand are calculated from the HH equation for monoprotic acids (Eq. (1a)). The intrinsic solubility, S0, wasdeveloped from the solubility-pH profile. Using the HHequation, the calculated curves were drawn for allexperimentally studied drugs.RESULTS AND DISCUSSIONThe pKa of an ionisable compound is an important property, describing the charge state of the drugat a certain pH. However, according to Avdeef [6], it isnot recommended to determine pKa values from thesolubility-pH measurements (pKaS). The results listedin Table 3 show a reasonably good agreementbetween the results obtained by the two differentmethods at two temperatures: from the solubility-pHmeasurements (pKaS), and with the precise spectrophotometric Bates-Schwarzenbach method (pKaB-S).PKaS nilai-nilai yang Diperoleh dari persimpangandua baris interpolated dari poin eksperimental untukSerikat dan terionisasi bentuk obat pilihan.Parameter dan korelasi koefisien terdaftardalam tabel 3. Semua data literatur nilai-nilai pKa,Diperoleh dengan metode yang berbeda (termasuk kita di298.2 K untuk perbandingan) yang disajikan dalam tabel 4.Umumnya, nilai-nilai lebih tinggi daripada dari sastra kecuali MEF. Dalam pendapat kamiBates-Schwarzenbach metode lebih tepatkarena tidak menggunakan pelarut bersama dan nilai-nilai extrapolated untuk larutan murni.Metode klasik goyang-labu diterapkanmengukur kelarutan keseimbangan pada dua suhuuntuk obat-obatan lima atas berbagai pH berkisar dari 2 sampai 8 atau 9.Waktu aduk dipilih sebagai 24 h pada saat yang samasuhu dan pH untuk mendapatkan hasil yang berulang.Setelah pengadukan, dua fase (solusi dan bahan solid) solusi jenuh dipisahkan, dansetelah 6 h (waktu yang diperlukan diperlukan untuk pemisahan dua fase) supernatant dibawa keluarkonsentrasi obat pengukuran olehSpektrometri HPLC-UV-Vis. Kelarutan HH teoritis, S, diperkirakan berdasarkan nilai-nilai Rifqi-Sdan solubilities intrinsik, S0 ditentukan olehgoyang-labu metode pada dua suhu. Datatercantum dalam tabel 4 bersama-sama dengan data sastra S0.Hasilnya akan dibahas untuk masing-masing obat secara terpisah.Flufenamic acidDuring the last few years there were differentvalues of pKa and S0 discussed in the literature attemperature 298.2 K for FLU. Our value of pKa = 4.62[20] is close to the presented by Muñoz et al. [27],pKa = 4.17 and higher than all remaining data. In ouropinion, the reason may also be insufficient control ofthe equilibrium temperature. The same parametersare responsible also for the values of the intrinsicsolubility, S0. The value obtained in this work at T =Table 3. The linear regression parameters, a1, b1 for the unionized form and a2, b2 for the ionized form, the corresponding correlationcoefficients, R1 and R2, the pKaS developed from the solubility-pH profile and the pKaB-S obtained from the Bates-Schwarzenbach method