Structure and Glass Transition Temperature of Amorphous Dispersions of Model Pharmaceuticals with Nucleobases from Molecular Dynamics.

Ctirad Červinka,Michal Fulem

doi:10.3390/pharmaceutics13081253

Ctirad Červinka, Michal Fulem

Open Access

https://doi.org/10.3390/pharmaceutics13081253

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Journal: Pharmaceutics	Publication Date: Aug 13, 2021
Citations: 8	License type: CC BY 4.0

Affiliation: University of Chemistry and Technology

Abstract

Glass transition temperature (Tg) is an important material property, which predetermines the kinetic stability of amorphous solids. In the context of active pharmaceutical ingredients (API), there is motivation to maximize their Tg by forming amorphous mixtures with other chemicals, labeled excipients. Molecular dynamics simulations are a natural computational tool to investigate the relationships between structure, dynamics, and cohesion of amorphous materials with an all-atom resolution. This work presents a computational study, addressing primarily the predictions of the glass transition temperatures of four selected API (carbamazepine, racemic ibuprofen, indomethacin, and naproxen) with two nucleobases (adenine and cytosine). Since the classical non-polarizable simulations fail to reach the quantitative accuracy of the predicted Tg, analyses of internal dynamics, hydrogen bonding, and cohesive forces in bulk phases of pure API and their mixtures with the nucleobases are performed to interpret the predicted trends. This manuscript reveals the method for a systematic search of beneficial pairs of API and excipients (with maximum Tg when mixed). Monitoring of transport and cohesive properties of API–excipients systems via molecular simulation will enable the design of such API formulations more efficiently in the future.

Highlights

Low solubility of crystalline active pharmaceutical ingredients (API) in water, often being hydrophobic molecules, represents a challenge to be faced in the development of most new drugs
As such amorphous phases are thermodynamically metastable and tend to crystallize, which diminishes the solubility again, artificial stabilization of amorphous API is often required to benefit from their higher solubility over a relevant time horizon [3]
To increase the validity of our force-field benchmarking, we included the α form of indomethacin, which is probably metastable at the given conditions [42]

Summary

Introduction

Low solubility of crystalline active pharmaceutical ingredients (API) in water, often being hydrophobic molecules, represents a challenge to be faced in the development of most new drugs To overcome this issue, API are often present in their amorphous solid phases in drug formulations [1,2]. Co-amorphous mixtures of the API with suitable low-molecular-weight natural compounds (sugars, amino acids, nucleobases, etc.), acting as excipients [6], are becoming the primary subject of research in this field [7,8]. Such a strategy is similar to using cryoprotective biomolecules for stabilization of biochemical samples at extreme conditions [9]

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