Crystallization process modifications to address polymorphic and particle size challenges in early stage development of an API salt

Malik, Abhishek; Hazra, Debasis; Steele, G.; Pal, Sharmistha

doi:10.1016/j.cherd.2020.09.021

Cited by 5 publications

(5 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This can lead to substantial variation in API physical attributes (PSD, morphology, etc.) between vendors and between batches . There may also be more prominent differences in impurity rejection …”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Polymorphs, Particle Size, and a Pandemic: Development of a Scalable Crystallization Process for Molnupiravir, an Antiviral for the Treatment of COVID-19

Bade,

Bothe,

Sirota

et al. 2023

Org. Process Res. Dev.

View full text Add to dashboard Cite

Molnupiravir is a small-molecule active pharmaceutical ingredient (API) prodrug of a nucleoside analog that was demonstrated to be efficacious for the treatment of patients with COVID-19. Early in the pandemic, Merck & Co. Inc. partnered with Ridgeback Biotherapeutics to accelerate the development of a manufacturing process for the drug in anticipation of high global demand for the treatment. It was essential to quickly establish a robust manufacturing process, as well as a rigorous physical attribute control strategy, to enable rapid delivery of metric tons of molnupiravir. Given the drug load of >50% (w/w) API in the formulation, there was high potential for the physical attributes to have a strong effect on drug product performance. Molnupiravir can also exist as multiple polymorphs and has the potential for wide variations in particle size. To address these challenges, we performed extensive derisking of these attributes with respect to the impact on drug product performance and were ultimately able to demonstrate the acceptability of a wide range of API physical attributes. In parallel, we strategically designed a scalable crystallization process that consistently delivered drug substance within our derisked range of attributes, across multiple manufacturing sites and scales. Thus, we were able to demonstrate that the API's physical attributes did not affect the drug product's critical quality attributes or therapeutic efficacy, giving our multiple manufacturing sites greater flexibility to deliver metric tons of molnupiravir to patients in need.

show abstract

Section: Resultsmentioning

confidence: 99%

“…between vendors and between batches. 28 There may also be more prominent differences in impurity rejection. 29 Prior to self-seeding, the batch is supersaturated and will hold some supersaturation before spontaneously nucleating.…”

Section: ■ Introductionmentioning

confidence: 99%

Polymorphs, Particle Size, and a Pandemic: Development of a Scalable Crystallization Process for Molnupiravir, an Antiviral for the Treatment of COVID-19

Bade,

Bothe,

Sirota

et al. 2023

Org. Process Res. Dev.

View full text Add to dashboard Cite

show abstract

“…Most chemical products or intermediates exist in a crystalline form, and crystallization is used to produce a wide variety of chemical, pharmaceutical, and food products . The main driving force for crystal nucleation and growth is supersaturation, which can be achieved by cooling, evaporation, and antisolvent methods, among others. , Compared to other purification processes, crystallization offers by high recovery, good product quality, high yield, low energy consumption, good operability, and good stability . However, the crystallization of PDAH, as a precursor of biobased PDI, has rarely been reported.…”

Section: Introductionmentioning

confidence: 99%

Thermodynamics, Solubility, and Crystallization of 1,5-Pentylenediamine Hydrochloride in Mixed Solvent Systems

Li,

Hu,

et al. 2024

Ind. Eng. Chem. Res.

View full text Add to dashboard Cite

The properties of 1,5-pentylenediamine hydrochloride (PDAH), a precursor of biobased pentamethylene diisocyanate (PDI), have a key influence on the PDI quality. In this study, the thermodynamics, solubility, and crystallization of PDAH in ethanol−water mixed solutions (0−100 wt % ethanol) were investigated. First, the solubility was investigated at 273.15− 323.15 K by a solvent evaporation method and characterized using the Apelblat, polynomial empirical, λh, and the modified van't Hoff−Jouyban−Acree equations. The activity coefficient increased with decreasing polarity and decreasing temperature. Thermodynamic analysis shows that dissolution is always spontaneous if the solution is not saturated. The surface tension and surface entropy factor increased with decreasing polarity and decreasing temperature. Finally, the crystallization of PDAH in an ethanol−water solution was studied by comparing cooling crystallization, antisolvent crystallization, and three combined cooling and antisolvent crystallization processes. The best crystallization process was found to be antisolvent, followed by cooling crystallization, with a 66.72% one-time yield and 99% purity. This study provides an important reference for the crystallization separation of other biobased products.

show abstract

“…Crystallization is an ancient separation process that is usually the last step in the purification process, and its control is crucial. Crystallization is a common and necessary unit operation in the chemical industry, and it is widely used in various industries, from the production of basic materials to complex pharmaceuticals ( Ms et al, 2020 ; Weng et al, 2020 ). Compared with other purification processes, crystallization has the advantages of high recovery rate, good quality of recovered solid-liquid products, high yield, low energy consumption, good operability, and good stability ( Sparenberg et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Separation, purification, and crystallization of 1,5-pentanediamine hydrochloride from fermentation broth by cation resin

Chen

Tang

et al. 2023

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

1,5-Pentanediamine hydrochloride (PDAH) was an important raw material for the preparation of bio-based pentamethylene diisocyanate (PDI). PDI has shown excellent properties in the application of adhesives and thermosetting polyurethane. In this study, PDAH was recovered from 1,5-pentanediamine (PDA) fermentation broth using a cation exchange resin and purified by crystallization. D152 was selected as the most suitable resin for purifying PDAH. The effects of solution pH, initial temperature, concentration of PDA, and adsorption time were studied by the static adsorption method. The equilibrium adsorption data were well fitted to Langmiur, Freundlich, and Temkin-Pyzhev adsorption isotherms. The adsorption free energy, enthalpy, and entropy were calculated. The experimental data were well described by the pseudo first-order kinetics model. The dynamic experiment in the fixed bed column showed that under optimal conditions, the adsorption capacity reached 96.45 mg g−1, and the recovery proportion of the effective section reached 80.16%. In addition, the crystallization of the PDAH solution obtained by elution proved that the crystal product quality of resin eluting solution was highest. Thus, our research will contribute to the industrial scale-up of the separation of PDAH.

show abstract

Crystallization process modifications to address polymorphic and particle size challenges in early stage development of an API salt

Cited by 5 publications

References 38 publications

Polymorphs, Particle Size, and a Pandemic: Development of a Scalable Crystallization Process for Molnupiravir, an Antiviral for the Treatment of COVID-19

Polymorphs, Particle Size, and a Pandemic: Development of a Scalable Crystallization Process for Molnupiravir, an Antiviral for the Treatment of COVID-19

Thermodynamics, Solubility, and Crystallization of 1,5-Pentylenediamine Hydrochloride in Mixed Solvent Systems

Separation, purification, and crystallization of 1,5-pentanediamine hydrochloride from fermentation broth by cation resin

Contact Info

Product

Resources

About