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Insights into Nano- and Micron-Scale Phase Separation in Amorphous Solid Dispersions Using Fluorescence-Based Techniques in Combination with Solid State Nuclear Magnetic Resonance Spectroscopy

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Abstract

Purpose

Miscibility between the drug and the polymer in an amorphous solid dispersion (ASD) is considered to be one of the most important factors impacting the solid state stability and dissolution performance of the active pharmaceutical ingredient (API). The research described herein utilizes emerging fluorescence-based methodologies to probe (im)miscibility of itraconazole (ITZ)-hydroxypropyl methylcellulose (HPMC) ASDs.

Methods

The ASDs were prepared by solvent evaporation with varying evaporation rates and were characterized by steady-state fluorescence spectroscopy, confocal imaging, differential scanning calorimetry (DSC), and solid state nuclear magnetic resonance (ssNMR) spectroscopy.

Results

The size of the phase separated domains for the ITZ-HPMC ASDs was affected by the solvent evaporation rate. Smaller domains (<10 nm) were observed in spray-dried ASDs, whereas larger domains (>30 nm) were found in ASDs prepared using slower evaporation rates. Confocal imaging provided visual confirmation of phase separation along with chemical specificity, achieved by selectively staining drug-rich and polymer-rich phases. ssNMR confirmed the results of fluorescence-based techniques and provided information on the size of phase separated domains.

Conclusions

The fluorescence-based methodologies proved to be sensitive and rapid in detecting phase separation, even at the nanoscale, in the ITZ-HPMC ASDs. Fluorescence-based methods thus show promise for miscibility evaluation of spray-dried ASDs.

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Abbreviations

AAPS:

Amorphous-amorphous phase separation

API:

Active pharmaceutical ingredient

ASD:

Amorphous solid dispersion

CP:

Cross polarization

CP-MAS:

Cross polarization magic angle spinning

DCM:

Dichloromethane

DSC:

Differential scanning calorimetry

HPMC:

Hydroxypropyl methyl cellulose

ITZ:

Itraconazole

MeOH:

Methanol

R6G:

Rhodamine-6-G

SD:

Spray drying

SEM:

Scanning electron microscopy

ssNMR:

Solid state nuclear magnetic resonance

T1 :

Laboratory frame relaxation time

T1rho :

Rotating frame relaxation time

Tg:

Glass transition temperature

TMS:

Tetramethylsilane

XRD:

X-ray diffraction

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Acknowledgments and Disclosures

Financial support to HSP from Migliaccio/Pfizer graduate fellowship is greatly acknowledged. The authors would like to thank the New Technology Review and Licensing Committee (NTRLC) at Merck & Co., Inc., Kenilworth, NJ, USA, for financial support. The authors would also like to thank Drs. Ellen C. Minnihan, Wei Xu, Anthony Leone, Timothy Rhodes, Andrew Latham and Christopher J. Welch for helpful discussions.

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Authors and Affiliations

  1. Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University,, West Lafayette, Indiana, 47907, USA

    Hitesh S. Purohit, Sugandha Saboo & Lynne S. Taylor

  2. Preformulation, MRL,, Merck & Co., Inc., Rahway, New Jersey, 07065, USA

    James D. Ormes & Matthew S. Lamm

  3. Preformulation, MRL,, Merck & Co., Inc., West Point, Pennsylvania, 19486, USA

    Yongchao Su

  4. Analytical Sciences, MRL,, Merck & Co., Inc., Rahway, New Jersey, 07065, USA

    Amanda K. P. Mann

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  1. Hitesh S. Purohit
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Correspondence to Lynne S. Taylor.

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Purohit, H.S., Ormes, J.D., Saboo, S. et al. Insights into Nano- and Micron-Scale Phase Separation in Amorphous Solid Dispersions Using Fluorescence-Based Techniques in Combination with Solid State Nuclear Magnetic Resonance Spectroscopy. Pharm Res 34, 1364–1377 (2017). https://doi.org/10.1007/s11095-017-2145-z

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