Antisolvent Crystallization of L-histidine in Micro-Channel Reactor under Microgravity

Zhang, Yan; Cheng, Jie; Glick, Yaïr; Samburski, Guy; Chen, Jie; Yang, Chao

doi:10.1007/s12217-019-09728-4

Cited by 6 publications

(5 citation statements)

References 26 publications

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“…It was demonstrated that the creation of small quantities of seed crystals in microgravity was sufficient for seeding similar polymorphs on Earth, facilitating lower resource requirements in the process. 80 Since this pivotal experiment, the company has demonstrated the efficacy of its microgravity-research enabling technology through 9 launches to space, comprising 2 autonomous nanosatellites and 7 round trips to the International Space Station (ISS). SpacePharma's microgravitybased lab platforms and crystallization processes are protected by several assigned patents and recognized by space agencies globally, including NASA, European Space Agency (ESA), Italian Space Agency (ASI), and Israel Space Agency (ISA).…”

Section: Enabling Technology For Mab Crystallization In Microgravitymentioning

confidence: 99%

Monoclonal Antibodies from Space: Improved Crystallization Under Microgravity During Manufacturing in Orbit

Amselem,

Kogan,

Loboda

et al. 2024

J Explor Res Pharmacol

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This article explores the significant improvements in manufacturing of monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs) enabled by the microgravity environment in orbiting space vehicles. mAbs, which are extensively incorporated into modern cancer treatments based on their ability to specifically target and kill tumor cells, traditionally require intravenous (IV) delivery. However, the inconvenience, potential risks of infection, and adverse systemic effects associated with IV administration have led to a move towards subcutaneous (SC) self-administration formulations. Current limitations hindering the development of SC injections are high viscosity and limited solubility of mAbs at high concentrations. The microgravity environment of space provides potential solutions to these challenges by promoting the formation of colloidal crystalline protein suspensions of low-viscosity and high concentration suitable for SC injection. Although conducting research and manufacturing in microgravity poses its own set of challenges, the benefits of improving the delivery, storage, and stability of mAbs are substantial. SpacePharma has developed novel, autonomous, remote-controlled, microfluidics-based lab-on-chip microgravity systems as a platform for the rapid screening and improved growth of crystallized monoclonal antibodies inside micron-size droplets. The advancements in this field have significant potential to improve patient care by enabling large-scale manufacturing of crystallized mAb therapies in the emerging space economy.

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Section: Enabling Technology For Mab Crystallization In Microgravitymentioning

confidence: 99%

Monoclonal Antibodies from Space: Improved Crystallization Under Microgravity During Manufacturing in Orbit

Amselem,

Kogan,

Loboda

et al. 2024

J Explor Res Pharmacol

View full text Add to dashboard Cite

show abstract

“…Early proof-of-concept demonstrations conducted on parabolic flights and on extended microgravity platforms such as the international space station (ISS) have demonstrated the potential benefits of in-space microgravity crystallization for better understanding polymorphism and for supporting pathfinding routes towards novel formulations (1)(2)(3)(4). Polymorphic control of active pharmaceutical ingredients is a key concern for safety, manufacturability, and dosing (5,6).…”

Section: Introductionmentioning

confidence: 99%

Return of the Ritonavir: A Study on the Stability of Pharmaceuticals Processed in Orbit

Bauser,

Smith,

Parent

et al. 2024

Preprint

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Despite notable progress in realizing the benefits of microgravity, the physical stability of therapeutics processed in space has not been sufficiently investigated. Environmental factors including vibration, acceleration, radiation, and temperature, if not addressed could impact the feasibility of in-space drug processing. The presented work demonstrates the successful recovery of the metastable Form III of ritonavir generated in orbit. The test samples and passive controls containing each of the anhydrous forms of ritonavir; Form I, Form II, Form III, and amorphous exhibit excellent stability. By providing a detailed experimental dataset centered on survivability, we pave the way for the future of in-space processing of medicines that enable the development of novel drug products on Earth and benefit long-duration human exploration initiatives.

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“…Some novel methods have also been reported. For example, Yang’s team obtained the metastable form B through antisolvent crystallization in a microchannel reactor under microgravity and a continuous mixed-suspension mixed-product removal crystallization setup, respectively. It is an effective method to regulate polymorphs by continuous crystallization, − but the ethanol–water mixing solvent was still used.…”

Section: Introductionmentioning

confidence: 99%

Selective Crystallization of l-Histidine Metastable Polymorphs: The Role and Mechanism of Additives

Wang,

Liu,

Wang

et al. 2024

Crystal Growth & Design

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L-Histidine forms A and B usually crystallize simultaneously in pure aqueous solution, posing a significant challenge in selectively obtaining one pure polymorph. In this study, we accomplished the selective crystallization of L-histidine form B using a strategy of additives. A series of additives with selective abilities were discovered and investigated. The results showed that the selective ability of the additives on L-histidine form B varied significantly with the lengths of the carbon chain and the types of substituent groups in the additives. Taking L-valine as a representative, the mechanism of selective crystallization of form B by additives was studied through solution NMR spectroscopy, combined with crystal structure analysis, density functional theory calculations, and molecular dynamics simulations. The results revealed that the additive is prone to bind to the −COO − group of Lhistidine through its −NH 3 + group. The difference in molecular stacking between form A and form B originates from their unique dimers (referred to as characteristic dimers in this paper). And the stability of the characteristic dimer of form B is stronger than that of form A in solution in the presence of additives. On the one hand, the additives exhibit a stronger inhibitory effect on the growth of form A with −COO − groups exposed on both sides of the a-axis compared to that of form B with −COO − groups exposed on one side of the a-axis. On the other hand, the addition of additives enhances the relative stability of the characteristic dimer of L-histidine form B compared to that of form A, which makes more of the smallest interacting units of form B in the solution for nucleation and growth. This study offers valuable insights into the crystallization of L-histidine in the pharmaceutical industry and provides guidance for the regulation of polymorphs by using additive strategies.

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Antisolvent Crystallization of L-histidine in Micro-Channel Reactor under Microgravity

Cited by 6 publications

References 26 publications

Monoclonal Antibodies from Space: Improved Crystallization Under Microgravity During Manufacturing in Orbit

Monoclonal Antibodies from Space: Improved Crystallization Under Microgravity During Manufacturing in Orbit

Return of the Ritonavir: A Study on the Stability of Pharmaceuticals Processed in Orbit

Selective Crystallization of l-Histidine Metastable Polymorphs: The Role and Mechanism of Additives

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