Date of Completion

5-3-2018

Embargo Period

4-20-2018

Keywords

amorphous nanoparticles, DoE, in vitro dissolution testing, spray drying, amorphous solid dispersion, miscibility, solid-state, interaction, thermodynamics, quality by design, nanocrystals, design of experiments, media milling, stability testing, nanoamorphous, sonoprecipitation

Major Advisor

Dr. Diane J. Burgess

Associate Advisor

Dr. Rajeev Gokhale

Associate Advisor

Dr. Bodhi Chaudhuri

Associate Advisor

Dr. Xiuling Lu

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

In the last few decades, the pharmaceutical industry has employed a quality by design (QbD) approach for conventional drug product development to minimize errors in product optimization and validation. Lately, this has been extended to novel pharmaceutical drug products (such as nanocrystalline and nanoamorphous drug products). The present research emphasizes the design and development of stable nanocrystalline and nanoamorphous formulations of BCS class II and II/IV drugs via a comprehensive QbD approach. This approach was used to identify, optimize, validate and control different critical process parameters and critical formulation parameters of solid nano-formulations. The objectives of this research were to: (1) investigate any correlation between critical process parameters and critical formulation parameters as well as critical quality attributes using a comprehensive QbD approach; (2) investigate the effect of temperature and relative humidity during accelerated and/or long term stability studies; and (3) investigate drug-stabilizer interaction mechanisms.

Based on proof-of-concept studies, BCS class II and II/IV drugs with different physicochemical properties were utilized for the successful development of stable and robust nanocrystalline and nanoamorphous formulations. Different top-down and bottom-up manufacturing techniques: wet media milling (nanocrystalline formulations); and sonoprecipitation (nanoamorphous formulations) followed by spray drying were used to prepare the solid nanoformulations. Based on the pre-formulation studies, drug-stabilizer interaction mechanisms were investigated via different solid-state tools (DSC, FTIR and PXRD). The DSC data was used to determine whether drug-stabilizer interactions occurred and the type of interaction was investigated using FTIR. PXRD was used to detect the solid-state form and any polymorphic transition in the drug-stabilizer complexes. Low and intermediate molecular weight polymers, high glass transition (Tg) sugars and anionic surfactants were determined to be the strong stabilizers during processing and storage stability of the solid nanoformulations. A quality by design approach was used to establish a correlation between critical process parameters, critical formulation parameters and critical quality attributes for the development of the robust solid nanoformulations. Critical process parameters related to manufacturing techniques: wet media milling (milling speed, milling time, pump speed); sonoprecipitation (ultra-sonication speed, time); and spray drying (inlet temperature, aspirator rate, feed flow rate) were investigated. Critical formulation parameters: drug and stabilizer concentrations were investigated. The process speed, time, inlet temperature, flow rates, drug concentrations and stabilizer concentration significantly affected the particle size and total product yield of the solid nanoformulations. Following the DoE studies, validation was performed to ensure reproducibility and robustness of different CQAs (particle size, total product yield, drug loading, moisture content and zeta potential) of solid nanoformulations prepared using the optimized and predicted process and formulation parameters. Stability studies were performed at three different conditions: 4°C, 25°C/60% RH and 40°C/75% RH for different time-points (1, 3, 6 and 12 month/s) to investigate the effect of temperature and relative humidity on the nanoamorphous and nanocrystalline formulations. Stability studies revealed the following trend: 4°C (most stable) > 25°C/60% RH > 40°C/75% RH (least stable) for the optimized spray-dried nanocrystalline and nanoamorphous formulations in terms of physicochemical attributes, crystallinity and in vitro dissolution testing. An array of orthogonal solid-state tools (DSC, ATR-FTIR, PLM, PXRD and AFM) were utilized to characterize the solid-state form (crystalline, amorphous, semi-crystalline and semi-amorphous) and polymorphic transitions in the freshly prepared solid nanoformulations and those stored at different stability conditions. Particle size distribution and moisture content analysis were performed via Zetasizer (ZS90) and Karl fisher titration, respectively. RP-HPLC was used to detect drug loading in the solid nanoformulations. The solid nano-formulations prepared via the comprehensive QbD approach resulted in a remarkably high total product yield (~70-80% w/w) with small, uniform and homogenous particle size (200-300 nm, 0.05-0.2 PDI). In vitro dissolution testing were performed to investigate the effect of pH, solid-state form, particle size, temperature and relative humidity on drug release from the solid nano-formulations. USP apparatus I and II were utilized to study and differentiate the drug release from the nanoamorphous and nanocrystalline formulations based on their solid-state form and particle size. Drug release from the solid nanoformulations followed a particle size dependent dissolution trend. Nanoamorphous and nanocrystalline formulations showed a high dissolution rate/kinetic solubility compared to the macro-sized formulations.

To sum up, the comprehensive QbD approach performed in the present research delineates an important and time-saving strategy to develop successful, robust and stable solid nanoamorphous and nanocrystalline formulations with the desired physicochemical attributes/CQAs, solid-state form and in vitro and/or in vivo performance.

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