Changes in the ionization state of pharmaceuticals – Solid and solution state conversion

Pharmaceutical salts are commonly used in the final solid dosage form. Altering the ionization state of the active pharmaceutical ingredients (APIs) may lead to several advantages including increased solubility and improved solid state properties relative to the neutral form. In addition, salt formation may be utilized to improve the chemical stability of the compound. Ionizable drug substances can form salts by coupling with counterions. However, the salt formation of weak acids/bases can be problematic due to the occurrence of disproportionation, the conversion of salt form back to its free form in the solid state. This conversion, which results in a change in ionization state of the API, can significantly affect solubility, solid state properties and chemical stability and thus can ultimately compromise the effectiveness of the drug. Although salt forms are widely utilized in the pharmaceutical industry, disproportionation in the presence of moisture and excipients is not well understood. This research aims to provide a fundamental understanding of disproportionation in the presence of moisture and thus assist formulators in making rational formulation and storage condition choices based on the API properties, instead of using a trial and error approach. This will avoid problems encountered later on during development and improve the safety and reproducibility of the final dosage form. This work shows that the properties of the salt, specifically pHmax and buffering capacity, play important roles in influencing the disproportionation tendency and that the storage conditions (temperature and relative humidity) as well as some aspects of formulation design (drug to excipient ratio and particle size) also have significant influence on the extent of disproportionation in the solid state. In addition, the link between chemical instability (specifically oxidation) and ionization state was demonstrated in this work. It was found that the free base of sertraline was prone to oxidation whereas its salt counterparts have superior stability against oxidation due to their ionized state. The change in ionization state occurs not only occur in solid state formulations as described above, but also takes place in the solution state. Due to the physiological pH variations in the human body, some ionizable compounds may be prone to the conversion from the ionized to an unionized form during delivery. Because the unionized form usually has lower solubility than the ionized form, ionizable compounds can be susceptible to supersaturation and subsequently precipitation when entering a pH environment that favors the formation of unionized species, with precipitation leading to a decrease in solution concentration. The decrease in solution concentration can impact the extent of absorption and in turn affect the bioavailability. It is thus critical to understand the pH-induced precipitation behavior of ionizable compounds and explore the possibility of utilizing formulation strategies to maintain higher solution concentrations following pH changes. For this work, a pH-metric titration method was utilized to study the precipitation behavior of several APIs. It was discovered that a compound\u27s solution behavior is strongly influenced by the solid state properties of the precipitate. Compounds that precipitated as a metastable form exhibit a prolonged supersaturation behavior whereas a short-lived supersaturation was observed for compounds that precipitate as the most stable crystalline form. In addition, the effectiveness of utilizing polymers to modify the pH-induced precipitation behavior of APIs was evaluated by measuring wide angle x-ray scattering (WAXS) of the precipitates using synchrotron radiation. Here, some polymers were found to change the precipitation behavior by inhibiting the formation of a crystalline precipitate. The use of synchrotron radiation to analyze the solid state properties of precipitates was demonstrated to be an effective approach that didn\u27t require large amounts of solid or extensive sample preparation