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Pharmaceutical Research

, 35:140 | Cite as

Polymorphic Transformation of Indomethacin during Hot Melt Extrusion Granulation: Process and Dissolution Control

  • Ting Xu
  • Kajalajit Nahar
  • Rutesh Dave
  • Simon Bates
  • Kenneth Morris
Research Paper Theme: Formulation and Manufacturing of Solid Dosage Forms
Part of the following topical collections:
  1. Formulation and Manufacturing of Solid Dosage Forms

ABSTRACT

Purpose

To study and elucidate the effect of the intensity and duration of processing stresses on the possible solid-state changes during a hot melt extrusion granulation process.

Methods

Blends of α-indomethacin and PEG 3350 (w/w 4:1) were granulated using various screw sizes/designs on the melt extruder under different temperature regimes. Differential Scanning Calorimetry and X-ray Powder Diffraction were employed for characterization. The dissolution behavior of the pure polymorphs and the resulting granules was determined using in-situ fiber optic UV testing system. An XRPD quantitation method using Excel full pattern fitting was developed to determine the concentration of each constituent (amorphous, α and γ indomethacin and PEG) in samples collected from each functioning zone and in granules.

Results

Analysis of in-process samples and granules revealed that higher temperature (≥130°C) and shear stress accelerated the process induced phase transitions from amorphous and/or the α form to γ indomethacin during heating stage. However, rapid cooling resulted in an increased percentage of the α form allowing isolation of the meta-stable form.

Conclusions

By determining the conditions that either prevent or facilitate process induced transformations of IMC polymorphs during melt granulation, a design space was developed to control the polymorph present in the resulting granules. This represents the conditions necessary to balance the thermodynamic relationships between the polymorphs of the IMC system and the kinetics of the possible transformations as a function of the processing stresses.

KEY WORDS

crystallization extrusion granulation process induced transformation solid state X-ray powder diffraction 

ABBREVIATIONS

API

Active pharmaceutical ingredient

DSC

Differential scanning calorimetry

GRG

Generalized reduced gradient

HME

Hot melt extruder

IMC

Indomethacin

PITs

Process induced transformations

XRPD

X-ray powder diffraction

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

We gratefully thank the Natoli Institute for Industrial Pharmacy Research and Development and Lachman Institute for Pharmaceutical Analysis, Long Island University, NY for financial support.

Supplementary material

11095_2017_2325_MOESM1_ESM.xlsx (18 kb)
ESM 1 (XLSX 17 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Ting Xu
    • 1
  • Kajalajit Nahar
    • 1
  • Rutesh Dave
    • 1
  • Simon Bates
    • 2
  • Kenneth Morris
    • 3
  1. 1.Department of Pharmaceutical Sciences, Arnold and Marie Schwartz College of PharmacyLong Island UniversityBrooklynUSA
  2. 2.Triclinic Labs Inc.LafayetteUSA
  3. 3.Lachman Institute for Pharmaceutical AnalysisLong Island UniversityBrooklynUSA

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