API pKa Study

Since most active pharmaceutical ingredients (APIs) have acidic and/or basic functional groups, their ionization state is controlled by the solution pH and acid dissociation constant (i.e., pKa). The degree of dissociation of APIs has an important impact on the prescription of generic drugs as well as their kinetic parameters, and is one of the physicochemical properties of interest. In general, the degree of dissociation of APIs greatly depends on the pH of the drug-containing medium, and the pH of the medium is often adjusted in the prescribing process to ionize the drug to a certain extent in order to meet the required drug solubility and formulation stability. The degree of dissociation of APIs also has an important effect on the absorption, distribution, and elimination of generic drugs. In general, dissociated drugs are less likely to be absorbed through biofilms, whereas non-dissociated drugs tend to pass efficiently through lipid-based biofilms. Based on the dissociation constants, it is possible to estimate the major drug species present in the environment (usually in the neutral pH range).

Figure 1. Dissociation equilibrium of sulfonamides. (Alyami, et al. 2017)

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Determination of the dissociation constant of API is particularly important for generic drugs and is important for drug solubility, stability, and absorption in the gastrointestinal tract. Alfa Chemistry provides professional solutions for API dissociation constant study, which can easily and quickly determine the pKa value of API with accuracy and reliability.

We can conduct process studies according to the characteristics of the dosage form, combined with the physicochemical properties and stability of the drug, taking into account the production conditions and equipment, initially determining the preparation process for laboratory samples, and establishing the corresponding process control indicators. We offer a wide range of pKa determination methods as described below, either using any of the individual techniques or multiple techniques.

Determination Methods of API pKa

Potentiometric Titration

We monitor the titration process by titrating the sample with acid or base using a pH electrode. The pKa value is calculated based on the change in the shape of the titration curve versus a blank titration curve without a sample.

Potentiometric titration is a highly accurate technique for determining API pKa values. Its disadvantages include the requirement to use one milligram of the pure compound and a mixture of aqueous buffer.

Spectrophotometry

During the titration process, spectral data are recorded continuously using a diode array spectrometer. The absorption spectrum of the sample changes during the titration to reflect the concentration of neutral and ionized substances present. The maximum change in absorbance occurs at the pKa value corresponding to the pH value.

The spectrophotometric method has a high degree of precision, as does the potentiometric method, but different spectra are required for different substances and the reagents must be pure. In order to use this method, the absorption spectra of individual substances must be characterized beforehand.

Liquid Chromatography (LC)

We offer the LC technique for the determination of pKa. This method requires only a small amount of the compound and the sample under study does not need to be pure. The disadvantage of this method is the pH of the mobile phase.

Capillary Electrophoresis

In this method, the API pKa value is obtained by fitting the effective mobility as a function of pH to a suitable model of the number of ionizable groups. This technique typically uses only a few ng or less of the compound for analysis, and only the ph-dependent mobility needs to be determined.

Applications for API pKa Study

• To speculate on the nature of the drug in terms of solubilization, dissolution, in vivo distribution, metabolism, and excretion
• Provide a reference for the research of prescription design and quality standard of generic drugs
• Provide a theoretical basis for generic drug development. Medicilon is a new drug discovery and development outsourcing company