Early processability assessments during product development can help identify optimal API for efficient processing

Downstream processability of crystal habit-modified active pharmaceutical ingredient

 

Authors

Nawin Pudasaini
Pratik P Upadhyay
Christian R Parker
Stefan U Hagen
Andrew D Bond§
and Jukka Rantanen*

Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, Denmark
Syntese A/S, Industriholmen 11-13, Hvidovre, Denmark
§Department of Chemistry, University of Cambridge, Cambridge, UK   


Summary

Efficient downstream processing of active pharmaceutical ingredients (APIs) can depend strongly on their particulate properties, such as size and shape distributions. Especially in drug products with high API content, needle-like crystal habit of an API may show compromised flowability and tabletability, creating significant processability difficulties on a production scale.

However, such a habit can be adapted to the needs of downstream processing. To this end, we modified the needle-like crystal habit of the model API 5-aminosalicylic acid (5-ASA). This study reports processability assessment of six representative crystal habits of 5-ASA (needles, plates, rectangular bars, rhombohedrals, elongated hexagons, and spheroids) in the context of direct compression using ring shear tester, flow rate analyzer, and Gamlen D series.

As expected, needles were very cohesive, had low flow rate (1.0 ± 0.08 mg/s), and low bulk density (0.14 ± 0.01 g/mL) but showed better tabletability, whereas the opposite was observed with more isotropic crystal habits. For instance, spheroids, elongated hexagons, and rhombohedrals were easy/free-flowing and had high bulk densities (≥0.5 g/mL), but final tablets had lower tensile strength than that of needles. Of the six crystal habits, the plates showed a good compromise considering both flowability and tabletability.

Introduction

Oral solid dosage forms constitute a major share of drug products manufactured across pharmaceutical industries.1 Such dosage forms are produced from heterogeneous powder blends containing an active pharmaceutical ingredient (API), where it typically contributes between 5 and 90% to the overall weight of the drug products. In the drug products with high API content, particulate properties of an API determine the

manufacturing processes to be used for downstream processing.2,3 For tablet manufacturing, direct compression (DC) is preferred over more complicated dry or wet granulation.4 However, DC demands good flowability and tabletability of powder blends. Furthermore, with the U.S. Food and Drug Administration (FDA) encouraging pharmaceutical industries to modernize small-molecule manufacturing using continuous

manufacturing concepts,5 DC makes the continuous manufacturing line much simpler6 with just two processing steps (blending and compression). To that end, particulate properties of an API must enable its DC. Although much effort is paid to control crystal forms and size distributions of an API, the crystal habit is often overlooked during “pure” polymorph screening. However, crystal habits can be adapted to the needs of downstream processing.

In general terms, a crystal habit refers to the external appearance of a crystal and has been used interchangeably with crystal shape or crystal morphology. The crystal habit of an API is known to influence its physicochemical,7 biopharmaceutical,8 and mechanical properties.9 Many APIs with anisotropic crystal habits, such as needles or flakes, present significant difficulties in downstream processing and can be difficult to formulate into

solid dosage forms due to its compromised flowability and tabletability.10 Generally, such processability challenges are overcome either by using large quantities of functional excipients or with additional processing steps like milling, granulation, as well as roller compaction. However, increasing excipient quantity can result in large-sized dosage forms and can negatively impact patient compliance.11 Furthermore, excipient overload may not cover the poor API properties in high drug load formulations. Additional corrective processing steps increase manufacturing costs as they incur more resources, energy, control, and time and can be deleterious to API physical stability. Consequently, eliminating non-valueadding operations has obvious advantages.

API properties responsible for its bulk behavior such as its solid forms, crystal size, and crystal habit can be predefined during the crystallization step. Extensive efforts have been made in understanding the API crystal growth and on the predictability of their crystal habits.12 In addition, several methods are established to manipulate crystal habits.13 These broadly include changing recrystallization solvents, the use of “tailor-made” small-molecule additives, or different types of macromolecules. However, such investigations typically end with generating multiple crystal habits and, very rarely, focus on identifying optimal habits for efficient downstream processing. Identifying an optimal crystal habit is essential; after all, different processes can demand different habits. For instance, isotropic shapes flow better,14 whereas such habits may not be optimal for tableting. With the availability of material-sparing instruments for processability assessment, such evaluation can be carried out in the laboratory phase of product development. This paper reports processability assessment of different crystal habits of the model API 5-aminosalicylic acid (5-ASA). As an anti-inflammatory agent, 5-ASA is used to treat inflammatory bowel diseases, which crystallizes out as needles under its typical crystallization conditions. To improve its downstream processability, we obtained alternative crystal habits of 5-ASA. This study is aimed at identifying the optimal crystal habit of 5-ASA in the context of direct compression.

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