Continuous Heterogeneous Crystallization on Excipient Surfaces

Abstract

A novel continuous heterogeneous crystallization process is developed in which the active pharmaceutical ingredient (API) is crystallized directly on the surface of an excipient within the crystallizer. The product is subsequently dried and formed into tablets without the need for complex downstream processing steps, such as milling, sieving, granulation, and blending. The aim is to eliminate many steps of the particle processing in drug product manufacturing. The APIs and excipients systems were selected by investigating heteroepitaxial mechanisms. The effects of various process parameters, such as temperature, residence time, and mode of operation, on drug loading were studied. Three different process designsmixed suspension mixed product removal with a traditional impeller, Viscojet mixing, and a fluidized bed crystallizerwere utilized for direct crystallization of the API on the surface of the crystalline excipient. The excipient selection and process design parameters have a significant impact on drug loading, avoidance of bulk nucleation and crystallization, control of API crystal shape and size, and process control. The maximum drug loading of the excipient with API in this study was 47%. Also, it was demonstrated that increasing the supersaturation ratio and residence time increased the drug loading. The products were collected from the crystallizer and directly compressed into tablet form. The tablet hardness and dissolution profile were also studied. The fully continuous process eliminates the downstream steps, resulting in the production of crystalline compounds and the final form (tablets) in a significantly faster, more efficient, and more economical manner with a smaller footprint. mentioned steps. 6−10 The precise final dosage, content uniformity, composition, mechanical properties, and critical quality attribute of every single tablet, which are highly regulated, 2,11−13 highly depend on the performance of the involved stages, for instance, component segregation, which can be caused by differences in particle size, density, or shape, and segregation in blending, hoppers, transfer lines, or feeders, and results in heterogeneity in tablet compositions. 14−17 Significant academic research and industrial development have been invested to overcome drug product line challenges and enable consistent manufacturing of high-quality tablets. 18−22 These challenges, and subsequent effects, are more problematic in the continuous manufacturing arena, 23,24 where the continuous flow of material, continuous workload of the drug product line, residence time distribution, and validation of "batches" of the final product enter into the design of already complicated processes. 17,20,21,23,24 Recent endeavors in shifting from the traditional batch pharmaceutical processes to the modern and emerging

Emerging role of primary heterogeneous nucleation in pharmaceutical crystallization

“…The utility of heterogeneous nucleation has also been demonstrated for continuous manufacturing, which is a cost‐effective technique widely adopted in the chemical and food industry (Yazdanpanah et al, ). Moreover, the regulatory agency (i.e., USFDA) has also included it as one of the emerging technologies and published a draft guidance on continuous manufacturing of pharmaceuticals in February 2019 (USFDA, ).…”

“…Novartis‐MIT Center for Continuous Manufacturing (MIT, ) (Massachuttes institute of technology) and EPSRC CMAC future manufacturing research hub (EPSRC, ) (University of Strathclyde, United Kingdom) have proposed that common pharmaceutical excipients could serve as a heteronucleant to assist continuous manufacturing of the pharmaceutical drug products. The process not only enables continuous manufacturing but also eliminates the steps of downstream processing (Yazdanpanah et al, ).…”

“…The excipient used as a heteronucleant can improve characteristics of API‐excipient, which can influence product characteristics or biopharmaceutical performance of the API. Improvement in downstream processing can include ease of filtration, elimination of sieving/blending (Yazdanpanah et al, ), improvement in flowability, better compressibility, and/or compactibility and superior dissolution of API (Arribas Bueno et al, ).…”

“…The utility of heterogeneous nucleation has also been demonstrated for continuous manufacturing, which is a cost-effective technique widely adopted in the chemical and food industry (Yazdanpanah et al, 2017). Moreover, the regulatory agency (i.e., USFDA) has also The process not only enables continuous manufacturing but also eliminates the steps of downstream processing (Yazdanpanah et al, 2017).…”

“…Primary heterogeneous nucleation offers a versatile approach for influencing the solid form using crystallization. Primary heterogeneous nucleants include but not limited to self-assembled monolayers (Yang & Myerson, 2015;Zhang et al, 2011), polymers (Price, Grzesiak, & Matzger, 2005), biocompatible small molecules (Yazdanpanah et al, 2017), functionalized surfaces (Parambil, Poornachary, Tan, & Heng, 2014), and surfaces with modified topography (Patel et al, 2016). Intentional or unintentional presence of heteronucleants can modulate nucleation or crystal growth.…”