An experimental study on polymorph control and continuous heterogeneous crystallization of carbamazepine

Hu, Chuntian; Testa, Christopher J.; Shores, Brianna T.; Wu, Wei; Shvedova, Khrystyna; Born, Stephen C.; Chattopadhyay, Saptarshi; Takizawa, Bayan; Mascia, Salvatore

doi:10.1039/c9ce00908f

Cited by 12 publications

(5 citation statements)

References 53 publications

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“…Carbamazepine (CBZ) is a BCS class II drug discovered in 1960 and used to treat epilepsy, neuropathic pain, and schizophrenia . There are four anhydrous forms of CBZ which have the following relative thermodynamic stabilities (at room temperature): III > I > IV > II. − An enantiotropic relationship between CBZ forms I and III has been determined, alongside a transition temperature of 71 °C between these two polymorphs . The solubility of these two polymorphs in simulated gastric fluids and particularly scCO 2 has been reported by Kalikin et al.…”

Section: Introductionmentioning

confidence: 94%

Investigating Process Variables and Additive Selection To Optimize Polymorphic Control of Carbamazepine in a CO₂ Antisolvent Crystallization Process

Long

Ryan

Padrela

2020

Org. Process Res. Dev.

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Supercritical CO2 antisolvent crystallization typically promotes the formation of metastable polymorphic forms of pharmaceutical drugs. However, using this technological approach in combination with the use of distinct molecular additives can provide further control over the final polymorphic form obtained. The work presented herein investigates the influence of critical processing variables of a CO2 antisolvent crystallization process in the presence of molecular additives with respect to the polymorphism of carbamazepine (CBZ), a highly polymorphic BCS class II drug. A Design of Experiments (DoE) approach was performed to assess the outcome of CBZ polymorphism, impacted by CO2 antisolvent processing variables such as pressure, temperature, and CO2 addition rate when anionic additives (sodium stearate or sodium dodecyl sulfate) were selected. Statistical analysis revealed that the combination of temperature and CO2 addition rate show statistically significant impact (p < 0.05) on the final CBZ polymorphic form obtained when no additive was present during short hold studies. However, when using 5% w/w additive in the CBZ methanol solutions, CBZ samples produced from CO2 antisolvent crystallization correspond to form II (when using sodium stearate as the additive) or form III (when using sodium dodecyl sulfate as the additive) for most samples, regardless of the processing conditions used. An investigation into the polymorphic stability of these CBZ samples was undertaken, allowing the precipitated CBZ to remain immersed in the supercritical media (supercritical CO2 and methanol) for a prolonged period (60 h). Carbamazepine samples that were initially form II began to convert to the stable form III at lower temperature (40 °C), while samples that were initially form III showed almost no conversion.

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Section: Introductionmentioning

confidence: 94%

Investigating Process Variables and Additive Selection To Optimize Polymorphic Control of Carbamazepine in a CO₂ Antisolvent Crystallization Process

Long

Ryan

Padrela

2020

Org. Process Res. Dev.

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“…Hu et al also tested different excipients (PVA, PVP, etc.) to alter the morphology of carbamazepine . In their work, they identified the significant process parameters which determined the polymorphism and overall morphology of the API in a single-stage MSMPR.…”

Section: Introductionmentioning

confidence: 99%

Development of Continuous Additive-Controlled MSMPR Crystallization by DoE-Based Batch Experiments

Stoffán,

Lőrincz,

Pusztai

et al. 2024

Ind. Eng. Chem. Res.

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Additive-controlled crystallization is a promising method to improve crystal morphology and produce solid drug particles with the desired technological and pharmacological properties. However, its adaptation to continuous operation is a hardly researched area. Accordingly, in this work, we aimed to come up with a methodology that provides the systematic and fast development of a continuous three-stage MSMPR cascade crystallizer. For that, a cooling crystallization of famotidine (FMT) from water, in the presence of a formulation additive, poly(vinylpyrrolidone) (PVP-K12), was developed. Process parameters with a significant impact on product quality and quantity were examined in batch mode through a 2 4−1 fractional factorial design for the implementation of additive-controlled continuous crystallization. These batch experiments represented one residence time of the continuous system. Based on the statistical analysis, the residence time (RT) had the highest effect on yield, while the polymer amount was critical from the product polymorphism, crystal size, and flowability points of view. The values of critical process parameters in continuous operation were fixed according to the batch results. Two continuous cooling crystallization experiments were carried out, one with 1.25 w/w FMT % PVP-K12 and one with no additive. A mixture of FMT polymorphs (Form A and Form B) crystallized without the additive through five residence times (>6.5 h) with 70.8% overall yield. On the other hand, the additive-controlled continuous experiment resulted pure and homogeneous Form A product with excellent flowability. The system could be operated for >6.5 h without clogging with a 71.1% overall yield and a 4-fold improvement in productivity compared to its batch equivalent.

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“…In addition to improved productivity, continuous crystallization has a number of distinct advantages over batch operation. Being able to reach a steady state during the crystallization process (something not possible in batch) results in greater reproducibility and consistency in the crystalline material and shows some advantages compared to batch in terms of control of polymorphic form and engineering of particle size distribution, in addition to a significant increase in productivity [ 8 , 9 , 10 ]. In addition, competitive steady states in continuous crystallizers have recently been demonstrated to provide a robust mechanism to produce both stable and metastable polymorphs at scale [ 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Integrated Purification and Formulation of an Active Pharmaceutical Ingredient via Agitated Bed Crystallization and Fluidized Bed Processing

et al. 2022

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Integrated API and drug product processing enable molecules with high clinical efficacy but poor physicochemical characteristics to be commercialized by direct co-processing with excipients to produce advanced multicomponent intermediates. Furthermore, developing isolation-free frameworks would enable end-to-end continuous processing of drugs. The aim of this work was to purify a model API (sodium ibuprofen) and impurity (ibuprofen ethyl ester) system and then directly process it into a solid-state formulation without isolating a solid API phase. Confined agitated bed crystallization is proposed to purify a liquid stream of impure API from 4% to 0.2% w/w impurity content through periodic or parallelized operations. This stream is combined with a polymer solution in an intermediary tank, enabling the API to be spray coated directly onto microcrystalline cellulose beads. The spray coating process was developed using a Design of Experiments approach, allowing control over the drug loading efficiency and the crystallinity of the API on the beads by altering the process parameters. The DoE study indicated that the solvent volume was the dominant factor controlling the drug loading efficiency, while a combination of factors influenced the crystallinity. The products from the fluidized bed are ideal for processing into final drug products and can subsequently be coated to control drug release.

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An experimental study on polymorph control and continuous heterogeneous crystallization of carbamazepine

Abstract: Influences of superstaturation, stirring, anti-solvent, and polymer type on polymorph are investigated.

Cited by 12 publications

References 53 publications

Investigating Process Variables and Additive Selection To Optimize Polymorphic Control of Carbamazepine in a CO₂ Antisolvent Crystallization Process

Investigating Process Variables and Additive Selection To Optimize Polymorphic Control of Carbamazepine in a CO₂ Antisolvent Crystallization Process

Development of Continuous Additive-Controlled MSMPR Crystallization by DoE-Based Batch Experiments

Integrated Purification and Formulation of an Active Pharmaceutical Ingredient via Agitated Bed Crystallization and Fluidized Bed Processing

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An experimental study on polymorph control and continuous heterogeneous crystallization of carbamazepine

Abstract: Influences of superstaturation, stirring, anti-solvent, and polymer type on polymorph are investigated.

Cited by 12 publications

References 53 publications

Investigating Process Variables and Additive Selection To Optimize Polymorphic Control of Carbamazepine in a CO2 Antisolvent Crystallization Process

Investigating Process Variables and Additive Selection To Optimize Polymorphic Control of Carbamazepine in a CO2 Antisolvent Crystallization Process

Development of Continuous Additive-Controlled MSMPR Crystallization by DoE-Based Batch Experiments

Integrated Purification and Formulation of an Active Pharmaceutical Ingredient via Agitated Bed Crystallization and Fluidized Bed Processing

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Product

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Investigating Process Variables and Additive Selection To Optimize Polymorphic Control of Carbamazepine in a CO₂ Antisolvent Crystallization Process

Investigating Process Variables and Additive Selection To Optimize Polymorphic Control of Carbamazepine in a CO₂ Antisolvent Crystallization Process