Acetic Acid as Processing Aid Dramatically Improves Organic Solvent Solubility of Weakly Basic Drugs for Spray Dried Dispersion Manufacture.

Molly Adam,Michael Grass,Michael Morgen,Warren Miller,Jonathan Cape,Amanda Pluntze,Aaron Stewart

doi:10.3390/pharmaceutics14030555

Molly Adam, Michael Grass + Show 5 more

Open Access

https://doi.org/10.3390/pharmaceutics14030555

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Journal: Pharmaceutics	Publication Date: Mar 2, 2022
Citations: 2	License type: CC BY 4.0

Affiliation: Lonza (United States)

Abstract

Many active pharmaceutical ingredients (APIs) in the pharmaceutical pipeline require bioavailability enhancing formulations due to very low aqueous solubility. Although spray dried dispersions (SDDs) have demonstrated broad utility in enhancing the bioavailability of such APIs by trapping them in a high-energy amorphous form, many new chemical entities (NCEs) are poorly soluble not just in water, but in preferred organic spray drying solvents, e.g., methanol (MeOH) and acetone. Spraying poorly solvent soluble APIs from dilute solutions leads to low process throughput and small particles that challenge downstream processing. For APIs with basic pKa values, spray solvent solubility can be dramatically increased by using an acid to ionize the API. Specifically, we show that acetic acid can increase API solubility in MeOH:H2O by 10-fold for a weakly basic drug, gefitinib (GEF, pKa 7.2), by ionizing GEF to form the transient acetate salt. The acetic acid is removed during drying, resulting in a SDD of the original GEF free base having performance similar to SDDs sprayed from solvents without acetic acid. The increase in solvent solubility enables large scale manufacturing for these challenging APIs by significantly increasing the throughput and reducing the amount of solvent required.

Highlights

It has been widely reported that an increasing fraction of new chemical entities (NCEs) in the pharmaceutical pipeline are poorly water soluble, and that many require solubilization technology to achieve high oral bioavailability [1,2]
Using acetic acid in small quantities as a processing aid for spray drying from MeOH
In this study we demonstrated the technology with the model compound gefitinib (GEF), and successfully manufactured amorphous spray dried dispersions (SDDs) using two different dispersion polymers and typical processing conditions

Summary

Introduction

It has been widely reported that an increasing fraction of new chemical entities (NCEs) in the pharmaceutical pipeline are poorly water soluble, and that many require solubilization technology to achieve high oral bioavailability [1,2]. Among several formulation approaches to improve the oral bioavailability of these challenging compounds, amorphous solid dispersions (ASDs) are enabling due to their ability to substantially increase dissolved drug concentrations, with enhancements ranging from 2 to 100 times the crystalline solubility, which can significantly increase absorption [3–9]. Spray drying has become the most common manufacturing technology for commercial production of pharmaceutical ASDs due to its broad applicability, scalability, and low temperature exposure due to evaporative cooling. Acetone and methanol (MeOH) are two preferred spray solvents, due to their high volatility, ability to dissolve a wide range of APIs and useful dispersion polymers, relatively low solution viscosity, equipment compatibility, and safety and environmental considerations [15].

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