Estimation of Effective pKa of Bicarbonate Buffer
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Observed Flux Predicted Without Surface pH Predicted With Surface pH Bulk pH Predicted Flux Without Surface pH Observed Flux Predicted (Buffer pKa: 4.20) Predicted (Buffer pKa: 3.55) Predicted (Buffer pKa: 6.05) Background The microenvironment pH at the dissolving particle surface, rather than the bulk pH, guides the pH-dependent solubility of the drug at the particle surface. Methods 1. Krieg, B.J., et al., Journal of pharmaceutical sciences, 2014. 103(11): p. 3473-3490. 2. Krieg, B.J., et al., Journal of pharmaceutical sciences, 2015. 104(9) : p. 2894-2904. Results and Conclusions As observed for all four drugs, when 6.05 is used as the pKa, the flux rates are higher and surface pH is closer to bulk pH - this is due to the high buffer capacity. When 3.55 is used as pKa, the flux is slower than observed due to very low buffer capacity. However, when an effective pKa of 4.2 is used, the observed data can be explained well. References Figure 2. Observed [2] and predicted flux, using different buffer pKa values, and their corresponding surface pH values for three acidic drugs and a basic drug at different bicarbonate buffer concentrations. Siri Kalyan Chirumamilla, David B. Turner, Masoud Jamei Certara UK Limited, Simcyp Division, Sheffield, United Kingdom [email protected] Estimation of Effective pK a of Bicarbonate Buffer However, carbonic acid is formed by hydration of dissolved carbon dioxide by water and the reaction rate constant for this step (Kc) is 10 6 – 10 10 times slower than the carbonic acid ionization constant (Ka1). Buffers of sufficient capacity neutralize the increased or decreased hydrogen ions in the diffusion layer, thereby making the surface pH equal to bulk pH. However, this capacity to neutralize differs from buffer to buffer, and in the mechanistic surface pH model, this depends both on the concentration and pKa of the buffer. Bicarbonate buffer is the weakest among the commonly used buffers and the pKa of carbonic acid ionization was experimentally determined to be 3.55 at 35°C. 2 3 1 + + 3 − 2 + 2 + + 3 − 2 + 2 ՞ 2 3 Therefore the hydration reaction is the rate limiting step and the overall reaction is given by If the reaction between CO 2 and H 2 O is instantaneous, the pKa of bicarbonate buffer would be 3.55, and if it is slow, the effective pKa of bicarbonate buffer would be 6.05. In addition, the effective pKa within the diffusion layer might be different from the bulk because the time the molecule spends in the diffusion layer (rapid dissolution) may be less than the reaction time; this could lead to different calculated dissolution flux rates than experimentally observed values [1]. In this work, we predict the effective pKa of bicarbonate buffer using which we can recover observed dissolution rates. Intrinsic disk dissolution rates/flux values are calculated using the Levich equation using surface solubility calculated using the mechanistic surface pH model originally implemented in Simcyp V14. The model is verified by predicting the intrinsic dissolution rates measured in the presence of phosphate buffer for three acidic and one basic drugs (Figure 1). A: Indomethacin, B: Ketoprofen, C: Ibuprofen, D: Haloperidol Figure 1. Observed [2] and predicted flux using of three acid drugs and a basic drug at different phosphate buffer concentrations. The work presented here was made possible, in part, by U.S. FDA grant 1U01FD005225-01. A B C D The apparent pKa of bicarbonate buffer in the mechanistic surface pH model was changed iteratively to match the observed Intrinsic dissolution rate in the presence of different concentrations of bicarbonate buffer. where Ka is the overall equilibrium reaction rate constant and the value of pKa was determined to be 6.05 [1]. A: Indomethacin B: Ketoprofen C: Ibuprofen D: Haloperidol
Transcript of Estimation of Effective pKa of Bicarbonate Buffer
Observed Flux Predicted Without Surface pH
Predicted With Surface pH
Bulk pH Predicted Flux Without Surface pH
Observed Flux Predicted (Buffer pKa: 4.20)
Predicted (Buffer pKa: 3.55) Predicted (Buffer pKa: 6.05)
Background
The microenvironment pH at the dissolving particle surface, rather than thebulk pH, guides the pH-dependent solubility of the drug at the particlesurface.
Methods
1. Krieg, B.J., et al., Journal of pharmaceutical sciences, 2014. 103(11): p. 3473-3490.
2. Krieg, B.J., et al., Journal of pharmaceutical sciences, 2015. 104(9) : p. 2894-2904.
Results and Conclusions
As observed for all four drugs, when 6.05 is used as the pKa, the flux ratesare higher and surface pH is closer to bulk pH - this is due to the high buffercapacity. When 3.55 is used as pKa, the flux is slower than observed due tovery low buffer capacity. However, when an effective pKa of 4.2 is used, theobserved data can be explained well.
References
Figure 2. Observed [2] and predicted flux, using different buffer pKa values, and theircorresponding surface pH values for three acidic drugs and a basic drug at differentbicarbonate buffer concentrations.
Siri Kalyan Chirumamilla, David B. Turner, Masoud Jamei
Certara UK Limited, Simcyp Division, Sheffield, United Kingdom
Estimation of Effective pKa of Bicarbonate Buffer
However, carbonic acid is formed by hydration of dissolved carbon dioxide bywater and the reaction rate constant for this step (Kc) is 106 – 1010 timesslower than the carbonic acid ionization constant (Ka1).
Buffers of sufficient capacity neutralize the increased or decreased hydrogenions in the diffusion layer, thereby making the surface pH equal to bulk pH.However, this capacity to neutralize differs from buffer to buffer, and in themechanistic surface pH model, this depends both on the concentration andpKa of the buffer.
Bicarbonate buffer is the weakest among the commonly used buffers and thepKa of carbonic acid ionization was experimentally determined to be 3.55 at35°C. 𝐻2𝐶𝑂3
𝐾𝑎1𝐻+ + 𝐻𝐶𝑂3
−
𝐶𝑂2 𝑎𝑞 + 𝐻2𝑂𝐾𝑎𝐻+ + 𝐻𝐶𝑂3
−
𝐶𝑂2 𝑎𝑞 + 𝐻2𝑂 ՞𝐾𝑐𝐻2𝐶𝑂3
Therefore the hydration reaction is the rate limiting step and the overallreaction is given by
If the reaction between CO2 and H2O is instantaneous, the pKa of bicarbonatebuffer would be 3.55, and if it is slow, the effective pKa of bicarbonate bufferwould be 6.05. In addition, the effective pKa within the diffusion layer mightbe different from the bulk because the time the molecule spends in thediffusion layer (rapid dissolution) may be less than the reaction time; thiscould lead to different calculated dissolution flux rates than experimentallyobserved values [1]. In this work, we predict the effective pKa of bicarbonatebuffer using which we can recover observed dissolution rates.
Intrinsic disk dissolution rates/flux values are calculated using the Levichequation using surface solubility calculated using the mechanistic surface pHmodel originally implemented in Simcyp V14. The model is verified bypredicting the intrinsic dissolution rates measured in the presence ofphosphate buffer for three acidic and one basic drugs (Figure 1).
A: Indomethacin, B: Ketoprofen, C: Ibuprofen, D: Haloperidol
Figure 1. Observed [2] and predicted flux using of three acid drugs and a basic drug atdifferent phosphate buffer concentrations. The work presented here was made possible, in part, by U.S. FDA grant 1U01FD005225-01.
A
B
C
D
The apparent pKa of bicarbonate buffer in the mechanistic surface pHmodel was changed iteratively to match the observed Intrinsic dissolutionrate in the presence of different concentrations of bicarbonate buffer.
where Ka is the overall equilibrium reaction rate constant and the value ofpKa was determined to be 6.05 [1].
A: IndomethacinB: Ketoprofen
C: IbuprofenD: Haloperidol
