Author ORCID Identifier

https://orcid.org/0000-0001-8585-0407

Year of Publication

2020

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Pharmacy

Department

Pharmaceutical Sciences

First Advisor

Dr. Eric J. Munson

Second Advisor

Dr. Younsoo Bae

Abstract

Magnesium stearate (MgSt) is the most commonly used pharmaceutical excipient and is present in over half the tablet formulations on the market. In spite of its popularity as an effective lubricant, it has been repeatedly recognized that there is significant variability between MgSt samples, which can cause inconsistent lubrication between batches of MgSt. The hypothesis of this research is that the batch-to-batch variability in tablet lubrication and dissolution observed in tablet formulations containing different MgSt samples can be correlated with differences in MgSt physicochemical properties (fatty acid salt composition, crystal hydrate form, particle size and surface area). Developing correlations between MgSt properties has been challenging in part because there has not been a reliable method for determining crystal form. Recently, 13C solid-state nuclear magnetic resonance (SSNMR) has been used to clearly identifying the MgSt crystal forms.

13C SSNMR is used extensively throughout this work to identify the crystal forms of samples of MgSt. Thermogravimetric analysis and dynamic scanning calorimetry were used as complimentary techniques to understand thermal behavior of the samples. MgSt is typically used in tablets at low levels (0.2-5%), leading to challenges with detection of MgSt in formulations. To enhance detection in SSNMR, samples of MgSt have been synthesized in the lab using 13C-labeled stearic acid. Specific surface area (SSA) results were determined using N2 and Kr adsorption with BET calculations, and samples were dried using nitrogen flow for various times. A discriminating dissolution method was developed to differentiate between MgSt samples with varying properties. Lubrication efficiency was performed using a Presster compaction simulator and tensile strength determination using diametrical compression.

Synthesis studies showed that the fatty acid composition and synthesis method affects the crystal form of MgSt produced, with higher stearic content preferring the dihydrate form. Temperature and humidity affect the form of MgSt and facilitate interconversion between forms. Drying MgSt was found to affect surface area results, with the dihydrate converting to the disordered form. Dissolution of indomethacin tablets containing various types of MgSt showed a strong dependence on particle size and surface area, with smaller particle size and higher SSA samples having slower dissolution rates. Fatty acid composition and hydrate form were investigated as secondary variables influencing dissolution, with fatty acid showing no correlation with dissolution. Lubrication efficiency and tabletability studies showed an effect of crystal form, with monohydrate and dihydrate forms showing good lubrication efficiency compared to the disordered form, but also poorer tabletability.

In conclusion, the potential for variability in the crystal form of MgSt was found to be an important property of MgSt. There is variability in the form produced from synthesis, as well as interconversion between forms. Temperature, humidity and drying conditions are particularly important in controlling the crystal form of MgSt, as this can impact formulation stability and storage conditions. The primary variable affecting dissolution is particle size and surface area, but crystal form is a potential secondary variable. The physicochemical properties of MgSt, particularly crystal form and surface area, showed trends with lubrication and dissolution. This highlights the importance of choosing a MgSt material with the desired crystal form and surface area properties to match the lubrication and dissolution requirements for the formulation.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2020.385

Funding Information

JLC was partially funded by a USP Global Fellowship from US Pharmacopeia in 2016.

JLC was partially funded by a Pre-Doctoral Fellowship in Pharmaceutics from the PhRMA Foundation in 2018 and 2019.

This work was partially funded through the National Science Foundation Industry/University Cooperative Research Center, Center for Pharmaceutical Development (IIP-1063879, IIP-1540011 and industrial contributions), 2015-2020.

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