Process Analytical Technology for Crystallization of Active Pharmaceutical Ingredients

Malwade, Chandrakant Ramkrishna; Qu, Haiyan

doi:10.2174/1381612824666180629111632

Cited by 13 publications

(10 citation statements)

References 95 publications

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“…The above‐mentioned properties determine not only the quality of the final medicine product but also the efficiency of the downstream operations, such as filtration, drying, and pharmaceutical manufacturing processes, e.g., tableting. The solubility and dissolution rate are key factors that may influence the bioavailability of the API .…”

Section: Introductionmentioning

confidence: 98%

Crystallization of Cephradine Polymorphs and Hydrates from Mixed Solvents of Methanol and Water

Østergaard

Diego

2019

Chem Eng & Technol

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Cephradine monohydrate (CPH) crystallizes with a needle-like shape which leads to severe agglomeration and slow filtration. Effects of different operating conditions on the particle size and shape as well as the filterability of the crystal products are described. The solubility and stability of one anhydrate of cephradine (CPA1) and CPH as a function of temperature and water activity was investigated in different methanol and water mixtures. A solvent-mediated transformation from CPH to CPA1 was observed at water mole fractions below 0.2-0.35 depending on the temperature. The crystallization behavior of CPH was studied by linear cooling and antisolvent crystallization. Lowering the cooling rate and addition of seeds led to an increase in particle size and improvement of filterability.

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Section: Introductionmentioning

confidence: 98%

Crystallization of Cephradine Polymorphs and Hydrates from Mixed Solvents of Methanol and Water

Østergaard

Diego

2019

Chem Eng & Technol

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“…Both are important parameters in solution crystallization processes. 18,23,24,30,39,47 In the presented study, three different batch cooling crystallization experiments were adapted from the literature focused on the evaluation of a Raman spectrometer using flufenamic acid (FFA) as the model compound. 20 Today, Raman spectroscopy is an established PAT in research and development and manufacturing.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, the CCSA combines four LED wavelengths, spanning the ultraviolet (UV) and near-infrared (NIR) region (280, 340, 600, 860 nm), and temperature measuring capabilities (thermocouple type R) in a 380 × 30 mm housing (length × diameter, 7 mm diameter at the probe head). , Our previous study demonstrated that the CCSA can accurately measure solution and suspension concentration in aqueous formulations. Both are important parameters in solution crystallization processes. ,,,,, …”

Section: Introductionmentioning

confidence: 99%

Real-Time Monitoring of Crystallization Processes Using a Novel Compact Composite Sensor Array

Feng Báez,

Soto-Bibiloni,

Stelzer

2023

Org. Process Res. Dev.

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Compact composite process analytical technology (PAT) probes have been identified as a priority to alleviate space constraints in milliliter-scale crystallizers to mitigate their impact on hydrodynamics. Real-time monitoring of the liquid and solid phases in crystallization processes is vital to ensure the critical quality attributes of the crystallized material, including consistently obtaining the solid form. In this proof-of-principle study, a compact composite sensor array (CCSA, 380 × 30 mm housing [length × diameter, 7 mm probe head diameter] that combines ultraviolet (UV) and near-infrared (NIR) features at four different wavelengths (280, 340, 600, and 860 nm) as well as temperature measuring capabilities was evaluated. Flufenamic acid (FFA), a polymorphic compound with an enantiotropic relationship between its forms I and III, was used as the model API. The results indicate that the CCSA similarly to an established Raman spectrometer monitors the significant inflection points (timestamps) for three batch cooling crystallization processes: (1) spontaneous nucleation, (2) seeded, and (3) solvent-mediated polymorphic phase transformation (SMPT). Ultimately, the data presented in this study prove that the CCSA might be used as a cost-effective process analyzer to routinely monitor qualitatively crystallization processes while addressing the need for compact PATs suitable for small-scale set-ups.

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“…Crystallization is a widely used purification technique for the manufacturing of active pharmaceutical ingredients (APIs) as well as intermediates. Crystallization as the final step in the manufacturing of APIs plays an important role in obtaining the desired critical quality attributes of APIs, which are very important for subsequent formulation processes and the performance of the final drug products . The critical quality attributes of APIs that are important to drug product performance include the chemical purity, optical purity, solid form (crystalline or amorphous), particle size, and particle shape.…”

Section: Introductionmentioning

confidence: 99%

“…Crystallization as the final step in the manufacturing of APIs plays an important role in obtaining the desired critical quality attributes of APIs, which are very important for subsequent formulation processes and the performance of the final drug products. 1 The critical quality attributes of APIs that are important to drug product performance include the chemical purity, optical purity, solid form (crystalline or amorphous), particle size, and particle shape. Generally, the amorphous form of APIs exhibits better dissolution properties, which are important to achieving high bioavailability for drugs with low aqueous solubility.…”

Section: Introductionmentioning

confidence: 99%

Antisolvent Crystallization of Indomethacin from a Ternary Solvent System with High Productivity, Better Polymorphism, and Particle Size Control

Malwade

2019

Org. Process Res. Dev.

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Antisolvent crystallization of Indomethacin (IMC), a nonsteroidal anti-inflammatory drug, from a ternary solvent system (acetone-methanol-water) has been investigated in this work. Acetonemethanol (66.5-33.5 wt%) binary mixture was selected as a solvent based on the solubility of IMC reported earlier. Water was selected as an antisolvent based on the solubility of IMC measured in acetone-methanol-water mixtures at 25 °C. Unseeded and seeded antisolvent crystallization was carried out for two initial concentrations of IMC (and) with stepwise addition of 0, 1 0, 2 antisolvent. The acetone solvate of IMC was crystallized during the unseeded experiments, while the desired γ-IMC was obtained with a bimodal particle size distribution (PSD) during the experiments seeded with γ-IMC. A significant increase in the productivity was observed because of increased crystal yield and faster crystallization kinetics as compared to the crystallization processes reported earlier for the production of γ-IMC. Finally, the feasibility of IMC particle size tuning through the solvent-antisolvent (dissolution-growth) addition cycles was demonstrated successfully.

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Process Analytical Technology for Crystallization of Active Pharmaceutical Ingredients

Cited by 13 publications

References 95 publications

Crystallization of Cephradine Polymorphs and Hydrates from Mixed Solvents of Methanol and Water

Crystallization of Cephradine Polymorphs and Hydrates from Mixed Solvents of Methanol and Water

Real-Time Monitoring of Crystallization Processes Using a Novel Compact Composite Sensor Array

Antisolvent Crystallization of Indomethacin from a Ternary Solvent System with High Productivity, Better Polymorphism, and Particle Size Control

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