Science

Development of Spectrometric Titration Method for pKa Determination of Drugs

Preliminary Abstract
Poor water solubility in newly developed drugs has proven to be a tremendous problem for drug developers. The acid-base dissociation constant, pKa, is a major physiochemical property that affects the absorption of drugs in the human gastrointestinal tract. The Zeeh Pharmaceutical ExperimentStation lab in the School of Pharmacy would like to develop a methodology to extract the pKa values of drugs with the use of an automatic titrator and UV-VIS spectrophotometer. A variety of drugs, including monoprotic, diprotic, and triprotic acids/bases, ampholytes, and zwitterions will be analyzed with the developed method in order to obtain their pKa values. The drug pKas will be calculatedafter running a regression analysis in Microsoft Excel with the measured absorbance spectrum values.
Introduction
An exceeding problem in the development of new drugs is their poor water solubility and concomitant slow dissolution. Poor water soluble drugs can dissolve so slowly in the human gastrointestinal tract that only a small fraction of the dose is absorbed into the bloodstream. Anotherlimiting factor in administering poor water soluble drugs is difficultly in delivering them by the parenteral route (e.g., IV). Upon intravenous dosing, low solubility drugs can precipitate at the injection site, causing pain, swelling, and prohibiting further injections from that site. An estimated thirty percent of molecules that reach development are rejected in the long run due to absorption,distribution, metabolism, and excretion problems (Avdeef, 2003). Thus, more money is spent on compounds that fail compared to those that pass requirements. One of the major physiochemical properties affecting their absorption from the GI tract and precipitation at injection sites is the acid-base dissociation constant or pKa (Kong, 2007). With vast variation, weak acids and bases ionize insolutions, depending on pH. Therefore, a drug’s pKa value affects the distribution of the chemicals in solution and their availability to enter biological reactions (Kong, 2007). The pKa of a drug relates the pH to the charge state of a molecule (Caliaro, 2001). This dissociation constant enables the ability to predict the absorption, distribution, and excretion of various medicinal drugs. Forexample, basic drugs may dissolve in the stomach pH of about 1-2, but precipitate at intestinal pH of about 5-6.5 if their pKa falls in the range of 2-5. Similarly, such drugs can precipitate at the physiological pH of 7.4. Thus, the accurate determination of acid-base dissociation constants is frequently required in many chemical and biochemical areas (Gorji, 2010).
The Zeeh PharmaceuticalExperiment Station lab in the School of Pharmacy has automated titration capability for potentiometric determination of pKa. For poor water soluble drugs that have sufficient UV-VIS Chromophores, the pharmaceutical lab would like to develop the capability to measure pKa values by combining the automated titrator with the UV-VIS spectrophotometer. The development of methodology for the measurement ofpKa values of acid and base drug molecules will be conducted with the use of the automatic titrator and UV-VIS spectrophotometer. Similar methods have proved to be very fast, accurate, and reproducible throughout various studies (Meloun, 2007). A wide range of drugs will be tested in order to develop methodology for various drug types. For example, monoprotic acids/bases, diproticacids/bases, zwitterions, and ampholytes will be tested. A monoprotic acid donates one proton (hydrogen atom) per molecule to an aqueous solution, while a monoprotic base can accept one proton per molecule in an aqueous solution (Figure 3.0). Diprotic acids and bases donate/accept more than one proton. Ampholytes are molecules containing both acidic and basic groups (Figure 4.0). Zwitterions are...