Quantification, Mechanism, and Mitigation of Active Ingredient Phase Transformation in Tablets

Abstract

Model tablet formulations containing thiamine hydrochloride [as a nonstoichiometric hydrate (NSH)] and dicalcium phosphate dihydrate (DCPD) were prepared. In intact tablets, the water released by dehydration of DCPD mediated the transition of NSH to thiamine hydrochloride hemihydrate (HH). The use of an X-ray microdiffractometer with an area detector enabled us to rapidly and simultaneously monitor both the phase transformations. The spatial information, gained by monitoring the tablet from the surface to the core (depth profiling), revealed that both DCPD dehydration and HH formation progressed from the surface to the tablet core as a function of storage time. Film coating of the tablets with ethyl cellulose caused a decrease in both the reaction rates. There was a pronounced lag time, but once initiated, the transformations occurred simultaneously throughout the tablet. Thus the difference in the phase transformation behavior between the uncoated and the coated tablets could not have been discerned without the depth profiling. Incorporation of hydrophilic colloidal silica as a formulation component further slowed down the transformations. By acting as a water scavenger it maintained a very "dry" environment in the tablet matrix. Finally, by coating the NSH particles with hydrophobic colloidal silica, the formation of HH was further substantially decelerated. The microdiffractometric technique not only enabled direct analyses of tablets but also provided the critical spatial information. This helped in the selection of excipients with appropriate functionality to prevent the in situ phase transformations.

Compression-Induced Polymorphic Transformation in Tablets: Role of Shear Stress and Development of Mitigation Strategies

“…In addition to providing a two-dimensional image, 2D-XRD enables rapid data collection, enhanced signal intensity, and potential reduction in errors because of preferred orientation because a substantial fraction of each diffraction ring is captured. 20 The overall goal of our research is to develop mechanistic insights into phase transformations induced when powders are compressed into tablets. Although we focus on a specific polymorphic transformation, the ideas can be extended to other compression-induced phase transformations (amorphous / crystalline [and vice versa]; stable / metastable polymorph).…”

Miniaturized Approach for Excipient Selection During the Development of Oral Solid Dosage Form

“…For the successful manufacturing of tablets, various excipients such as binders, diluents, disintegrants, and lubricants are needed. Although excipients are considered as inactive ingredients and are added to improve the functionality of the dosage forms, they may have deleterious effect on the performance of the dosage forms at various stages during manufacturing, storage, and/or dissolution . This may be attributed to various properties of excipients such as water‐sorbing potential, phase transformation behavior, hydrophobicity, solubility, microenvironment pH, crystallinity, and chemical incompatibility with active pharmaceutical ingredient (API) .…”

“…Thus, it is important to investigate the influence of excipients on the performance of oral solid dosage forms as early as possible during development to identify and avoid performance‐related issues attributed to the excipients. A well‐designed excipient screening study during early development can help selecting suitable excipients that improve the functionality of the API . Also, it can help in the elimination of excipients having deleterious effect on the performance of API and/or find the solutions to mitigate the issues attributed to the excipient …”

Mid-Infrared Laser Spectroscopy Applications in Process Analytical Technology: Cleaning Validation, Microorganisms, and Active Pharmaceutical Ingredients in Formulations

“…This study concluded that accuracies and precisions obtained using MIR laser spectroscopy are comparable to NIR spectroscopy [44,45], Raman spectroscopy [46,47], and attenuated total reflection (ATR) infrared spectroscopy [48]. Other process analytical technology (PAT) applications of MIR laser spectroscopy are cleaning validation of pharmaceutical and biotechnology industrial batch reactors and other processing equipment [19], determination of API levels in tablets and formulations [49,50], and vibrational circular dichroism [51].…”