Structural evolution of indomethacin particles upon milling: Time‐resolved quantification and localization of disordered structure studied by IGC and DSC

doi:10.1002/jps.21986

Journal of Pharmaceutical Sciences

Volume 99, Issue 4, April 2010, Pages 1968-1981

https://doi.org/10.1002/jps.21986 Get rights and content

Abstract

The amorphization of indomethacin was induced by milling. The mass fraction of the amorphous phase in the drug milled for various time intervals was determined with differential scanning calorimetry (DSC). Because the surface fraction amorphized by milling can be much higher than the mass fraction, which can have a large impact on the powder properties, a method for quantification of surface fraction amorphized by milling using inverse gas chromatography (IGC) was developed. A calibration curve was constructed by mixing completely amorphous indomethacin (obtained after milling for 120 min) with various amounts of the initial crystalline sample. Linear part of the curve was then used to quantify the surface amorphous content of samples milled for different time intervals. Surface and mass amorphization kinetics were determined and fitted to a first‐order model. It was found that the surface amorphization rate is an order of magnitude higher than the mass amorphization rate. Results confirmed that IGC is a sensitive method for detection and quantification of the fraction of amorphous surface of milled indomethacin powder. If suitably combined with other techniques, this method represents a relatively general approach for the localization and quantification of the surface amorphous fraction in crystalline substances that transform into amorphous ones upon intensive milling. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1968–1981, 2010

Section snippets

INTRODUCTION

It is well established that drugs can exist in various solid forms: crystalline and amorphous. Particle size reduction obtained through milling is one of the most commonly used processes applied to crystalline powders. Such processes can modify the structural properties of the initial materials; that is, they can induce polymorphic transformations that are reflected in important biopharmaceutical effects associated with solubility, dissolution rate, or bioavailability, and influence powder

Materials

Crystalline γ‐indomethacin (Sigma‐Aldrich Chemie GmbH, Steinheim, Germany) was used as received. Test solvents for IGC measurements were hexane, heptane, octane, nonane, and decane (Ridel de Haën AG, Sleelze, Germany). Methane (Messer, Ruše, Slovenia) was used as a noninteracting standard in IGC experiments. Helium (Messer) was used as a carrier gas.

Sample Preparation

A ball mill (MM 301, Haan, Retsch, Germany) was used to mill the original crystalline sample, using a 15 mL stainless steel grinding jar with two

Electron Microscopy

Although electron microscopy gives only qualitative information about the crystalline and milled indomethacin samples, it suggests that morphological changes may occur in correlation with structural changes. γ‐indomethacin consists of plate‐like particles with smooth surfaces of different sizes (Fig. 1A). After milling for 20 s the sample has already changed and a small portion of the surface has become rough. The amount of changed surface structure increases with milling time (Fig. 1B–F). The

CONCLUSION

The efficiency of IGC as a method for the quantification of the fraction of amorphous surface of milled indomethacin was established. It was shown that the combination of IGC with DSC enables not only quantification but also the localization of structural changes of milled indomethacin; that is, it enables differentiation between the transformed structure at the surface of the particles and transformations of the bulk region. Care must be taken if the transformation process includes extensive

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Research ArticlesStructural evolution of indomethacin particles upon milling: Time‐resolved quantification and localization of disordered structure studied by IGC and DSC

Abstract

Section snippets

INTRODUCTION

Materials

Sample Preparation

Electron Microscopy

CONCLUSION

Int J Pharm

Int J Pharm

J Pharm Sci

Int J Pharm

Int J Pharm

J Chromatogr A

Int J Pharm

Int J Pharm

Eur J Pharm Sci

J Pharm Sci

J Pharm Sci

Int J Pharm

Solid State Phys

Eur J Pharm Sci

J Pharm Sci

Int J Pharm

J Non‐Cryst Solids

J Pharm Sci

J Pharm Sci

J Pharm Sci

Eur J Pharm Sci

What is the true solubility advantage for amorphous pharmaceuticals?

Pharm Res

Glassy state of pharmaceuticals. II. Bioinequivalence of glassy and crystalline indomethacin

Chem Pharm Bull

Research Articles
Structural evolution of indomethacin particles upon milling: Time‐resolved quantification and localization of disordered structure studied by IGC and DSC