Ionization States in the Microenvironment of Solid Dosage Forms: Effect of Formulation Variables and Processing

Abstract

The environment experienced by a drug in the final solid dosage form will be influenced by the nature of the excipients, the extent of their surfaces available for interaction, surface modification during processing and the amount and nature of solvent used.

Surface Acidity and Solid-State Compatibility of Excipients with an Acid-Sensitive API: Case Study of Atorvastatin Calcium

“…The ratios of the Kubelka-Munk functions, F(R), at the peaks corresponding to the ionized and unionized forms of the indicator (peak height ratios) were determined using a UV visible spectrophotometer (Cary 100 Bio) equipped with a diffuse reflectance accessory (Labsphere, model DRA-CA-30I). A pH eq value for each excipient was determined using the peak ratio in the solid samples and the peak ratio-solution pH relationships constructed for the corresponding indicator in buffered aqueous solutions (9). Table I lists the lactone levels in API-excipient mixtures after 6 weeks of storage at 40°C/25% RH and 50°C/20% RH.…”

“…The probe indicator method is more difficult from the measurement perspective and also has more experimental variables. These issues were addressed by Pudipeddi et al (12) and also in our earlier publications (9,11). For example, any particular probe molecule would cover only a narrow acidity range, and several indicators with different pK a values may be needed to measure acid-base properties of different excipients.…”

“…Alternatively, measurements are performed with solid materials, in which acid-base properties of the material are evaluated by monitoring protonation-dependent properties of various probe molecules with a corresponding detection method. Detection methods depend on the nature of a probe molecule and include NMR (2), fluorescence (3), attenuated total reflectance Fourier transform infrared spectroscopy (4), evanescent wave cavity ring-down spectroscopy (5), electron spin resonance (6), inverse gas chromatography (7), and diffuse reflectance visible spectroscopy (9)(10)(11). The last method usually utilizes common pH indicators (i.e., sulfonephthalein probe molecules) and represents the most common approach for pharmaceutical systems.…”

“…The last method usually utilizes common pH indicators (i.e., sulfonephthalein probe molecules) and represents the most common approach for pharmaceutical systems. In these measurements, the acidity of the solids has been expressed either as pH equivalent (pH eq ) (8)(9)(10) or Hammett acidity function, H 2− (11), where, by convention, the subscript, 2−, refers to the charge of the basic form of indicator. The pH eq of the solid surface is defined as the pH of an aqueous solution in which the ratio of the peak absorbance signals of the ionized to the unionized forms of the indicator is the same as in the given solid sample.…”

“…Limitations of both the approaches to measure apparent acidity for pharmaceutical solids have been discussed earlier (9,11,12). However, this is not a problem unique to solids; many liquid systems, such as mixed solvents and aqueous solutions with high salt or acid concentrations, do not have an established, thermodynamically rigorous, proton activity scale (13).…”