Influence of Carbamazepine Dihydrate on the Preparation of Amorphous Solid Dispersions by Hot Melt Extrusion.

Xiangyu Ma,Michael Lowinger,Felix Müller,Robert O Williams,Rebecca Schooler,Siyuan Huang,Xu Liu

doi:10.3390/pharmaceutics12040379

Abstract

Amorphous solid dispersions (ASDs) are commonly used in the pharmaceutical industry to improve the dissolution and bioavailability of poorly water-soluble drugs. Hot melt extrusion (HME) has been employed to prepare ASD based products. However, due to the narrow processing window of HME, ASDs are normally obtained with high processing temperatures and mechanical stress. Interestingly, one-third of pharmaceutical compounds reportedly exist in hydrate forms. In this study, we selected carbamazepine (CBZ) dihydrate to investigate its solid-state changes during the dehydration process and the impact of the dehydration on the preparation of CBZ ASDs using a Leistritz micro-18 extruder. Various characterization techniques were used to study the dehydration kinetics of CBZ dihydrate under different conditions. We designed the extrusion runs and demonstrated that: 1) the dehydration of CBZ dihydrate resulted in a disordered state of the drug molecule; 2) the resulted higher energy state CBZ facilitated the drug solubilization and mixing with the polymer matrix during the HME process, which significantly decreased the required extrusion temperature from 140 to 60 °C for CBZ ASDs manufacturing compared to directly processing anhydrous crystalline CBZ. This work illustrated that the proper utilization of drug hydrates can significantly improve the processability of HME for preparing ASDs.

Highlights

The increasing number of poorly water-soluble drug candidates continues to present challenges to pharmaceutical product development [1]
We investigated the effects of CBZ dihydrate on the preparation of CBZ amorphous solid dispersions (ASD) by hot melt extrusion (HME) and demonstrated that the utilization of in-situ dehydration of CBZ dihydrate can significantly reduce the temperature required for amorphization during the Pharmaceutics 2020, 12, 379
The results demonstrate the hypothesis that the polymer matrices should be in a ready-to-mix state before the dehydration of CBZ dihydrate to achieve CBZ ASDs

Summary

Introduction

The increasing number of poorly water-soluble drug candidates continues to present challenges to pharmaceutical product development [1]. In the last two decades, ASDs have gained popularity in the pharmaceutical industry, and their importance to solving drug solubility challenges for enhancing bioavailability of drugs is exemplified by the fact that 27 ASD based products have been approved by the Food and Drug Administration (FDA) [5] Various techniques such as spray drying [7], hot melt extrusion (HME) [8], Kinetisol® dispersion [9], and thin film freezing [10] have been developed and investigated to prepare ASDs. As one of the commercially used techniques, HME has been applied in the pharmaceutical industry to 14 ASD based products [5]. There is a need to expand this narrow processing window of HME to allow its applications for more poorly water-soluble drugs in the pharmaceutical industry [16]

Methods

Results

Conclusion