Development and manufacture of novel amorphous Itraconazole drug products using quality by design principles

The aim of this thesis was to improve the poor solubility of Itraconazole (ITZ) through novel approaches to product development using continuous manufacture with novel in-line process analytical technology (PAT) to monitor quality. The solubility parameter () of ITZ and polymers, Kollidon® VA64 (KOL), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and polyvinylacetate (PVA) were screened using group contribution theories developed by Fedors, Van Krevelen and Just-Breitkreutz. The difference in the solubility parameter (Δδ) indicated better miscibility for the ITZ-KOL, ITZ-HPMCAS systems (< 5 (MPa)1/2). The interaction parameters () were theoretically and experimentally calculated for ITZ-KOL, ITZ-HPMCAS, and ITZ-PVA. ITZ-KOL was the only system that demonstrated a linear correlation between the  and the reciprocal temperature (R2 of 0.8613), therefore was used to construct the solubility-miscibility phase diagram using Flory-Huggins model of thermodynamics of polymer solution. The metastable region on the phase diagram indicated ITZ drug load below 50% and temperatures between 140-160 ºC would produce stable and homogenous ITZ and KOL amorphous solid dispersions (ITZ-KOL-ASD). Sequential Design of Experiments approach (DoEs) for screening, optimisation and robustness was adopted to manufacture ITZ-KOL-ASDs using continuous hot melt extrusion (HME) and in-line ultraviolet-visible (UV-Vis) spectroscopy. DoE 1 screened the ITZ concentration, die temperature, screw speed and feed rate as critical factors. Ten out of eleven samples analysed passed the quality target for lightness, L* > 83%. Two shifts were observed in the absorbance spectra: a shift in the UV region from low to high wavelength and a shift in the baseline of the spectra. Principal component 1 (PC1) explained 86% of the variation which suggested the shift seen in UV region was caused by the increase in ITZ concentration. Shift in baseline was due to oversaturation and/or presence of bubbles. Only the ITZ concentration exhibited a statistically significant effect on the responses (absorbance and L*). DoE 2 explored the effect of screw speed and feed rate factors on the responses. Out of the ten samples only one failed due to feeding overshoot. L* was 84 ± 1% for the nine samples that passed the quality target with only screw speed being statistically significant for the absorbance response. PC1 accounted for 85.3%, which was due to the small shift in the UV region from low to high screw speeds (200 to 400 rpm). The absorbance at 370 nm (upper limit 0.6) and torque (upper limit 19 N·m) responses were used to build the design space (DS) as they were statistically significant. Validation and verification studies were conducted on random points within the DS where all conditions should meet the quality target product profile (QTPP). ITZ-KOL-ASD samples produced with the optimised conditions of 30% ITZ, 150°C, 300 rpm, 7g/min were found to be stable over 4 months at accelerated conditions. The shift seen in the in-line UV-Vis spectra from (369 to 375 nm) was addressed through analysis of in-line spectra of 0.01 to 1% ITZ-KOL-ASDs, along with density function theory (DFT) calculations of ITZ. The liquid crystal nature of ITZ and shear from extrusion were found to not influence the shift. Functional PC1 explained 91% of the dataset which was due to the shift in spectra when the concentration of ITZ changed from 0.01 to 1%. Structure of ITZ were optimised at the DFT/ B3LYP/6-31G* level and the rotamer M0158 (maximum energy) was found at 336.23 nm with a coiled conformation and rotamer M0373 (minimum energy) at 346.42 nm with planer conformation. Fourier transform infrared (FTIR) confirmed that the C-O stretching vibrations (1072 to 977 cm-1) were present with higher intensities in rotamer M0373. Experimentally, the sharp C-O peak at 945 cm-1 was only found in the 20% ITZ-KOL-ASDs. This confirmed the presence of the M0158 (coiled) rotamer at lower concentrations (1%) and M0373 (planer) at higher concentrations (20%) and provided evidence of the in-line shift being due to conformational changes of ITZ. A novel strategy for the compaction of immediate release tablets of ITZ-KOL-ASDs using inorganic salts (sodium chloride, potassium chloride, potassium dihydrogen orthophosphate, potassium bromide, and potassium bicarbonate) was investigated. ASD tablets compacted with potassium chloride (KCl) achieved tensile strength (TS) above 1.7 MPa at compression pressure of 200 MPa and disintegration of 4 minutes and so was investigated further. To attain optimised tablet formulations of round and oblong ITZ-KOL-ASDs, different proportions of Avicel®pH102 (MCC;10-30%), Tablettose®70 (TAB70; 2.6-32.6%) and KCl (5-15%) were explored, through the mixture design approach. Out of the seven formulation combinations compacted, MCC had a dominant effect on the formulations at higher levels of 30%. Tablets with 10–15% KCl and MCC less than 20% disintegrated within 2 (oblong) and 4 minutes (round). A DS was achieved for both tablet shapes, with limits set to TS more than 1.7 MPa and disintegration time less than 15 minutes to meet the quality target product profile (QTPP). Within the DS an optimised formulation (11.9% KCl, 21.43% MCC and 14.26% TAB70) was compacted and 100% drug release was achieved in 30 minutes during dissolution, in comparison to the corresponding ASD formulation with no KCl (21% release) and a formulation of the physical mixture with crystalline ITZ (7% release). The enhanced drug release profile was due to the kosmotropic effect of the salt which prevented the gelation of the polymer by competing for the water and therefore promoting quicker disintegration. This thesis demonstrated the use of in-line UV-Vis spectroscopy to continuously produce and monitor novel ITZ ASDs with enhanced solubility and showed new strategies to develop ITZ ASD tablet products which can achieve fast disintegration and dissolution through the adaptation of QbD principles underpinned by science.

Name dc:type.qualificationname

PhD

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

De Montfort University

Year dc:date.issued

2023

Author dc:creator

• Triboandas, Hetvi

Licence

• https://dora.dmu.ac.uk/bitstreams/07197eec-cca4-49db-be44-e8c4301b2487/download