Statistical methodology for scale-up of an anti-solvent crystallization process in the pharmaceutical industry

Tulcidas, Ameessa; Nascimento, Susana; Santos, B.A.V.; Álvarez, Carlos Márquez; Pawlowski, Sylwin; Rocha, Fernando

doi:10.1016/j.seppur.2018.12.019

Cited by 17 publications

(15 citation statements)

References 21 publications

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“…VIF is based on the square of the multiple correlation coefficient resulting from regressing a predictor variable against all other predictor variables. 28 If a variable has a strong linear relationship with at least one other variables, the correlation coefficient would be close to 1, and VIF for that variable would be large. The results of VIF measurements are displayed in Fig.…”

Section: Test For Multicollinearity: Variance Inflation Factor (Vif)mentioning

confidence: 99%

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Quantitative Microscopy: Particle Size/Shape Characterization, Addressing Common Errors Using ‘Analytics Continuum’ Approach

Saravanan

Muthudoss

Khullar

et al. 2021

Journal of Pharmaceutical Sciences

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Particle size/shape characterization of active pharmaceutical ingredient (API) is integral to successful product development. It is more of a correlative property than a decision-making measure. Though microscopy is the only technique that provides a direct measure of particle properties, it is neglected for reasons like non-repeatability and non-reproducibility which is often attributed to a) fundamental error, b) segregation error, c) human error, d) sample randomness, e) sample representativeness etc. Using the "Sucrose" as model sample, we propose "analytics continuum" approach that integrates optical microscope PSD measurements complimented by NIR spectroscopy-based trending analysis as a prescreening tool to demonstrate sample randomness and representativeness. Furthermore, plethora of statistical tests are utilized to infer population statistics. Subsequently, an attribute-based control chart and bootstrap-based confidence interval was developed to monitor product performance. A flowchart to serve as an elementary guideline is developed, which is then extended to handle more complex situations involving API crystallized from two different solvent systems. The results show that the developed methodology can be utilized as a quantitative procedure to assess the suitability of API/excipients from different batches or from alternate vendors and can significantly help in understanding the differences between material even on a minor scale.

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Section: Test For Multicollinearity: Variance Inflation Factor (Vif)mentioning

confidence: 99%

“…Consequently, selection of one particle descriptor from these parameters could pose concerns. 27,28 Hence, to select the best particle descriptor, exploratory data analysis is carried out.…”

Section: Test For Multicollinearity: Variance Inflation Factor (Vif)mentioning

confidence: 99%

Quantitative Microscopy: Particle Size/Shape Characterization, Addressing Common Errors Using ‘Analytics Continuum’ Approach

Saravanan

Muthudoss

Khullar

et al. 2021

Journal of Pharmaceutical Sciences

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“…23 The work presented herein is an extension of a previous study that addresses an antisolvent crystallization process. 25 In the latter, the impact of typical operational parameters such as the percentage of volume occupied by the suspension in the reactor as well as the agitation on the particle size was assessed. Usually, during the development of antisolvent crystallization processes, parameters such as the batch size and stirring speed are tested the most, and no (or less) attention is given to the suspension height to clearance ratio.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the current work was performed for a proof-of-concept, aiming to understand if varying clearance, along with power per volume, could influence the particle size parameters (Dv10, Dv50, Dv90) of an API obtained by antisolvent crystallization. For this purpose, a DoE approach was applied, and the experimental data were analyzed by previously developed modeling approach, 25 involving the use of multiple linear regression (MLR), to investigate possible correlations among the aforementioned parameters. Moreover, an additional goal of this work was to use the acquired experimental data to develop a methodology which aids in calculating a safe operational zone where an API with particle size within specification could be produced; this methodology can be then employed in more complex models.…”

Section: Introductionmentioning

confidence: 99%

Quality by Statistical Control in Crystallization—Assessment of Mixing Conditions and Probability of Obtaining the Desired Particle Size

Tulcidas

Santos

Pawlowski

et al. 2019

Ind. Eng. Chem. Res.

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Reactor hydrodynamics can play a significant role in antisolvent crystallizations. In this work, the impact of suspension height/clearance ratio (H/C) and power per volume (PV) on the particle size distribution (PSD) parameters Dv10, Dv50, and Dv90 of an active pharmaceutical ingredient (API) were evaluated. The API solution was added near the liquid surface of the antisolvent with a buret, at a rate of approximately 5 mL/min, between the impeller and the reactor’s wall. Statistical models were developed, and it was found that PSD parameters seem to be influenced by the H/C and PV. A relationship between the PSD parameters and the nucleation rate was also witnessed. Furthermore, different mathematical methodologies (indicator function and Monte Carlo simulations) were used to obtain a design space comprising the probability of success of having PSD parameters within specification. An operating region comprising the probability of success was estimated, which can aid in minimizing the risk of failure in antisolvent crystallization processes and consequently help reduce the financial losses caused by out-of-specification batches.

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“…Many industrial products are unable to meet specific industrial needs due to limitations of production process conditions, so subsequent processing of the products is necessary. In this paper, ODA was purified by the method of sublimation [20][21][22][23] and anti-solvent crystallization [24][25][26]. Compared to solution crystallization, sublimation crystallization is a solvent-free process that is not a solution-solvent interaction, but mainly molecular-molecular interactions, temperature, and supersaturation are often significant control factors.…”

mentioning

confidence: 99%

Crystallization and Purification of 4,4′‐Diaminodiphenyl Ether

Chen

Han

et al. 2020

Chem Eng & Technol

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The purification of 4,4 -diaminodiphenyl ether (ODA) was investigated. ODA, which contained impurities, was sublimated and anti-solvent (ethanol)-crystallized in N-dimethylformamide (DMF). Fourier transform infrared (FTIR) results revealed that the sublimated crystal was basically identical with the pure ODA sample. The influence of different amounts of ethanol on particle size distribution was analyzed during anti-solvent crystallization. The morphology of the ODA crystal was examined by scanning electron microscopy (SEM). The color of the sample enhanced from a brown powder to a colorless granular crystal. The purity of the sample could be increased from about 30 % to 87 %. With the operations of sublimation and anti-solvent crystallization, the purity, crystal morphology, and particle size distribution of ODA were significantly improved.

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Statistical methodology for scale-up of an anti-solvent crystallization process in the pharmaceutical industry

Cited by 17 publications

References 21 publications

Quantitative Microscopy: Particle Size/Shape Characterization, Addressing Common Errors Using ‘Analytics Continuum’ Approach

Quantitative Microscopy: Particle Size/Shape Characterization, Addressing Common Errors Using ‘Analytics Continuum’ Approach

Quality by Statistical Control in Crystallization—Assessment of Mixing Conditions and Probability of Obtaining the Desired Particle Size

Crystallization and Purification of 4,4′‐Diaminodiphenyl Ether

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