A Co-Processed API Approach for a Shear Sensitive Compound Affording Improved Chemical Stability and Streamlined Drug Product Processing

Abstract

The physical properties of active pharmaceutical ingredients (API) are critical to both drug substance (DS) isolation and drying operations, as well as streamlined drug product (DP) processing and the quality of final dosage units. High aspect ratio, low bulk density, API 'needles' in particular are a hindrance to efficient processing, with a low probability that conventional crystallization routes can modify the challenging morphology. The compound evaluated in this manuscript demonstrated this non-ideal morphology, with the added complexity of shear sensitivity. Modest shear exposure resulted in conversion of the thermodynamically stable crystalline phase to the amorphous phase, with the amorphous phase then undergoing accelerated chemical degradation. Slow filtration during DS isolation resulted in uncontrolled and elevated amorphous levels, while subsequent DP operations including blending, densification and compression increased amorphous content still further. A chemically stable final dosage unit would ideally involve a high bulk density, free flowing API that did not require densification in order to be commercialized as an oral dosage form with direct encapsulation of a single dosage unit. Despite every effort to modify the crystallization process, the physical properties of the API could not be improved. Here, an innovative isolation strategy using a thin film evaporation (TFE) process in the presence of a water soluble polymer alleviated filtration and drying risks and consistently achieved a high bulk density, free flowing co-processed API amenable to direct encapsulation. Characterization of the engineered materials suggested the lower amorphous levels and reduced shear sensitivity were achieved by coating surfaces of the API at relatively low polymer loads. This particle engineering route blurred conventional DS/DP boundaries that not only achieved improved chemical stability but also resulted in a optimized material, with simplified and more robust processing operations for both drug substance and drug product.

Continuous Manufacturing of Active Pharmaceutical Ingredients: Current Trends and Perspectives

“…[26] Other separation methods that are being actively researched include continuous liquid-liquid extractions, [27,28] filtration, [29,30] and evaporation processes. [31] Liquid-liquid extractions (LLE) can be achieved continuously using membrane technology in conjunction with filtration. One LLE example is the extraction of carbazate hydrazones.…”

Mechanoactivation as a Tool to Assess the Autoxidation Propensity of Amorphous Drugs

“…On the other hand, mechanical impaction applied to solids has been reported to enrich free radicals after amorphization of the solid, which could have profound implications, especially to their oxidative stability . This is also exemplified for amino acids such as cystine, alanine, arginine, celluloses, and solid polymers where the purity of the solid phase post-milling remains a concern .…”

Enhancement of material attributes of poorly compressible metformin hydrochloride through coprocessing with hydroxypropyl cellulose (HPC-L) using coprecipitation (CPT)

“…The improved functionalities in coprocessed APIs enable first hand application of direct compression by bypassing granulation in first place and enable continuous manufacturing (Paul 2023; Erdemir 2022). In some cases, coprocessed APIs also exhibit improved solubility, dissolution rate, and stability (Schenck et al 2021). Coprocessing methodologies used by the pharmaceutical industry are discussed in detail in recent publications and can be categorized into three main types: before crystallization, during crystallization, and after crystallization (Schenck et al 2020).…”