Chemometric study of the excipients’ influence on polymorphic-behavior. Mefenamic acid as case of study

Abstract

The assessment of polymorphism is a problematical issue for regulatory agencies, because variations among crystalline forms of active pharmaceutical ingredient (API) can lead to changes in the efficacy and safety of formulated product. Such conversions are very hard to be detected, thus, the development of techniques for the identification, characterization and quantification of polymorphs results essential in all stages of the manufacturing process. The presence of excipients in formulated products may change the crystal stability of an API, by catalyzing a polymorphic transformation or stabilizing the less stable form. As paradox, all suitable analytical techniques (spectroscopies, thermal analysis, NMR and DRX, and others) for polymorphic analysis are affected by excipients. A deep understanding of the polymorphism-excipient relationship is in full accordance with Quality by Design (QbD) paradigm, the systematic approach focused in quality building into a product based in the full understanding of the products and process. In this work, a novel approach based on thermal stress, MIR monitoring, multivariate curve resolution with alternating least squares (MCR-ALS) and kinetic analysis was developed and applied to monitor polymorphism behavior of model API in formulated products. Commercial tablets, physical mixtures and commercial API, were processed and analyzed under the proposed approach. Commercial tablets of MFA revealed a fast conversion to Form II, contrasting to the behavior of the pure API. Physical mixtures showed similar behavior to commercial tablets, thus reduction in transformation times was related to MFA-excipients physical interaction, even at surface level. Calorimetric studies support the conclusion obtained. The developed approach could be extended to others APIs and other stress sources (humidity, solvents, mechanical forces and its combinations), being a valuable tool for QbD environment.

Quality assessment of oral antimalarial and antiretroviral medicines used by public health systems in Sahel countries

“…In previous studies done in Sahel countries, substandard CQ medicines were detected by dissolution test failures or lower and greater API content detection than the labelled dose [ 20 , 21 ]. However, it was not possible to define the cause of these failures as the technical data sheet was not available to study the API polymorphism changes under accelerated conditions due to the potential API-excipients interactions [ 55 ].…”

Solid Form and Phase Transformation Properties of Fexofenadine Hydrochloride during Wet Granulation Process

“…Previously, some literatures reported that the phase transformation occurred in active ingredients or excipients could affect the final product performance [8,[33][34][35]. Therefore, in addition to identify the existence of phase transformation, it is also important to determine how it affects product performance.…”

A Process Analytical Technology (Pat) Approach to Evaluate Gabapentin Distribution in Laminar Extrudates

“…Consequently, it is crucial to monitor the polymorphic form of the API and confirm the stability or the conversion of that form throughout the process of manufacturing of the drug product. Particularly critical is the potential effect of temperature, moisture or pressure, often required for the transformation of a mixture of solid materials into a dosage form, on an unstable polymorphic form of the drug substance [2,19,25]. Most of the active pharmaceutical ingredients, especially newly synthesized molecular entities present low water solubility and consequently their bioavailability and therapeutic efficacy are inappropriate.…”