Determination of API Crystalline State in Hot Melt Extrudate Formulations

ABSTRACT

Purpose

The crystalline state of Fenofibrate was investigated using X-ray powder diffraction (XRPD) and Raman spectroscopy to determine the lowest concentration of crystalline Fenofibrate detectable for a series of physical mixtures in Kollidon® VA64 polymer, and in OptiMelt™ hot melt extrudate formulations containing 13% and 20% Fenofibrate in Kollidon® VA64 polymer.

Introduction

As increasing numbers of poorly soluble drug candidates are developed for commercialization, these candidates often pose challenging formulation development projects. For many of these candidates, novel formulation strategies are employed to develop scale-able formulations and stable products to ensure efficacy of the dosage form for the patient. Catalent’s OptiMelt™ hot melt extrusion platform provides a formulation strategy to generate solid dispersions of crystalline and amorphous drug candidates with amorphous excipients to stabilize the API in a polymer matrix. It is the structure and stability of this API/polymer matrix that is pivotal for the development of stable and efficacious products. As the drug-polymer homogeneity is known to be one of the critical parameters regarding the stability of the solid dispersions1, the experiments conducted in this study were designed to examine the nature of API in this polymer structure.

This study focused on an analytical approach to understand the state of the API in the context of hot melt extrusion formulations. Specifically, XRPD was used to determine the lowest concentration of crystalline API detectable using a given set of parameters for a series of physical mixtures of Fenofibrate in Kollidon® VA64 polymer, and also as extruded HME formulations containing 13% and 20% Fenofibrate in Kollidon® VA64 polymer. These same systems were then evaluated using Raman Spectroscopy to assess the lowest concentration of crystalline API that was detectable using a second analytical technique. These two tools were then employed to assess if the physical state of the API in the 13% and 20% Fenofibrate in Kollidon® VA64 polymer HME extrudates could be determined. Lastly, Raman mapping studies were conducted to determine the homogeneity of the API distribution in the polymer matrix.

Methods

XRPD studies were conducted on a Bruker D8 Advance, X-ray powder diffractometer system with Bragg-Brentano geometry and LynxEye XE Position Sensitive Detector. FT-Raman spectra were collected using a Nicolet NXR9650 Spectrometer equipped with 1064 nm Nd:YVO4 excitation laser, InGaAs detector and a MicroStage. Dispersive Raman micro-spectroscopy mapping studies were performed using a Nicolet Almega XR dispersive system equipped with a 633nm excitation and an automated confocal microscope (Olympus BX51). Fenofibrate was purchased by Catalent. Kollidon® VA64 polymer excipient was sourced from BASF. Hot melt extrusion was performed using a Rondol 10mm (40:1 L:D) co-rotating twin screw extruder with a single hole die, and an 18mm Leistritz ZSE 18HPe (40:1 L:D) twin screw extruder. Screw configuration with similar kneading and conveying elements was used on both extruders. Processing temperatures for the Fenofibrate/ Kollidon® VA64 preparations were selected based on manufacturing experience with these materials. The 0.2, 1, 2, 5, 10, 25 and 50% Fenofibrate in Kollidon® VA64 physical mixtures were prepared in vials and shaken to prepare uniform mixtures. The 13% Fenofibrate in Kollidon® VA64 HME sample was obtained from the 10mm Rondol extruder, while the 20% Fenofibrate inVA64 HME sample was obtained fromthe 18mm Leistritz extruder. Both extrudate samples were ground in a mortar and pestle to generate representative powders.

Results

XRPD and Raman analyses showed excellent responses for the 0.2% to 50% Fenofibrate/ Kollidon® VA64 physical mixtures with detection of crystalline Fenofibrate down to 0.2%. Refer to data in Table 1 and Figures 1 and 2 for Raman and XRPD data, respectively.

t1 f1 f2

 

Data in Table 2 shows that the 20% Fenofibrate HME extrudate did not show presence of crystalline API due to the observation of the broad halo associated with amorphous materials, indicating that the API contained in the API/polymer matrix was amorphous. Refer to data in Table 2 and Figure 3 for XRPD data showing the amorphous character.

T2 f3

Data in Table 3 shows that the 13% Fenofibrate in Kollidon® VA64 HME extrudate does not show a response at the 1650cm-1 peak consistent with crystalline API, but does exhibit a shifted peak near 1655cm-1 associated with the amorphous Fenofibrate in Kollidon® VA64 polymer. Refer to data in Table 3 and Figure 4 for Raman spectra.

T3 F4

Both data sets confirm the processing of 13% and 20% Fenofibrate in Kollidon® VA64 formulations generated from the 10mm and 18mm extrusion lines produced solid dispersions containing amorphous Fenofibrate. In addition, Raman mapping studies were conducted to confirm that the 13% and 20% Fenofibrate extrudes generated on both the 10mm and 18mm extruders were homogeneous2 and represented well-formed solid dispersions. Refer to Figure 5 for a Raman mapping image of the 13% extrudate analysis.

F5

CONCLUSIONS

• Crystalline Fenofibrate in Kollidon® VA64 physical mixtures can be detected as low as 0.2% by both dispersive Raman and Bragg-Brentano XRPD geometry.

• XRPD confirmed the amorphous nature of Fenofibrate in 13% and 20% API in Kollidon® VA64 HME extrudates, with Raman observing shifted responses for amorphous Fenofibrate in these HME extrudates and no observation of the crystalline Fenofibrate phase.

• Raman mapping studies showed homogeneity of Fenofibrate in both the 13% and 20% hot melt extrudates.

• Uniform, homogeneous solid dispersions of amorphous Fenofibrate were successfully generated using the OptiMelt™ hot melt extrusion platform.

 

REFERENCES

1. Qian, F. et al., Int. J. Pharm. 395, 2010, 232 235.

2. Vajna, B. et al., Int. J. Pharm. 419, 2011, 107 113.

ACKNOWLEDGEMENTS

Stephen Carino, Catalent Pharma Solutions (Morrisville, NC, USA), and Holger Cortes, Bruker AXS, Inc. (Madison, WI, USA) are acknowledged for providing Raman spectroscopic and XRPD analyses, respectively.

 

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