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Faster to First-time-in-Human: Prediction of the liquid solid ratio for continuous wet granulation.
Eur J Pharm Sci. 2022 May 01; 172:106151.EJ

Abstract

In early development, when active pharmaceutical ingredient (API) is in short supply, it would be beneficial to reduce the number of experiments by predicting a suitable L/S ratio before starting the product development. The aim of the study was to decrease development time and the amount of API needed for the process development of high drug load formulations for continuous twin-screw wet granulation (TSWG). Mixer torque rheometry was used as a pre-formulation tool to predict the suitable L/S ratios for granulation experiments. Three different values that were based on the MTR curves, were determined and assessed for their ability to predict the suitable L/S ratio for TSWG. Three APIs (allopurinol, paracetamol and metformin HCl) were used as model substances in high drug load formulations containing 60% drug substance. The MCC-mannitol ratio was varied to assess the optimal composition for the high-dose formulations. The API solubility affected the mixer torque rheometer (MTR) curves and the optimum L/S ratio for TSWG. The highly soluble metformin needed a much lower L/S ratio compared with allopurinol and paracetamol. A design space was determined for each API based on granule flowability and tablet tensile strength. The flowability of the granules and tensile strength of the tablets improved with an increasing L/S ratio. The MCC-mannitol filler ratio had a significant effect on tabletability for paracetamol and metformin, and these APIs having poor compaction properties needed higher MCC ratios to achieve the 2 MPa limit. The MCC-mannitol ratio had no effect on the granule flow properties. Instead, API properties had the largest influence on both granule flow properties and tensile strength. Based on this study, both the L/S ratio and MCC-mannitol ratio are crucial in controlling the critical quality attributes in high drug load formulations processed by TSWG. The optimum flow and tablet mechanical properties were achieved when using 75:25 MCC-mannitol ratio. Both start of the slope and 2/3 of the L/S ratio at the maximum torque in MTR provided a solid guideline to aim for in a TSWG experiment.

Authors+Show Affiliations

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.Early Product Development and Manufacturing, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca Gothenburg, 431 83 Mölndal, Sweden.Early Product Development and Manufacturing, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca Gothenburg, 431 83 Mölndal, Sweden.Early Product Development and Manufacturing, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca Gothenburg, 431 83 Mölndal, Sweden.Early Product Development and Manufacturing, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca Gothenburg, 431 83 Mölndal, Sweden.Early Product Development and Manufacturing, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca Gothenburg, 431 83 Mölndal, Sweden.School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.Early Product Development and Manufacturing, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca Gothenburg, 431 83 Mölndal, Sweden. Electronic address: pirjo.tajarobi@astrazeneca.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

35217210

Citation

Junnila, Atte, et al. "Faster to First-time-in-Human: Prediction of the Liquid Solid Ratio for Continuous Wet Granulation." European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, vol. 172, 2022, p. 106151.
Junnila A, Wikström H, Megarry A, et al. Faster to First-time-in-Human: Prediction of the liquid solid ratio for continuous wet granulation. Eur J Pharm Sci. 2022;172:106151.
Junnila, A., Wikström, H., Megarry, A., Gholami, A., Papathanasiou, F., Blomberg, A., Ketolainen, J., & Tajarobi, P. (2022). Faster to First-time-in-Human: Prediction of the liquid solid ratio for continuous wet granulation. European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, 172, 106151. https://doi.org/10.1016/j.ejps.2022.106151
Junnila A, et al. Faster to First-time-in-Human: Prediction of the Liquid Solid Ratio for Continuous Wet Granulation. Eur J Pharm Sci. 2022 May 1;172:106151. PubMed PMID: 35217210.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Faster to First-time-in-Human: Prediction of the liquid solid ratio for continuous wet granulation. AU - Junnila,Atte, AU - Wikström,Håkan, AU - Megarry,Andrew, AU - Gholami,Aida, AU - Papathanasiou,Foteini, AU - Blomberg,Andreas, AU - Ketolainen,Jarkko, AU - Tajarobi,Pirjo, Y1 - 2022/02/23/ PY - 2021/10/22/received PY - 2022/01/21/revised PY - 2022/02/21/accepted PY - 2022/2/27/pubmed PY - 2022/4/1/medline PY - 2022/2/26/entrez KW - Critical quality attribute KW - L/S ratio KW - Mannitol KW - Microcrystalline cellulose KW - Mixer torque rheometer KW - Twin-screw wet granulation SP - 106151 EP - 106151 JF - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JO - Eur J Pharm Sci VL - 172 N2 - In early development, when active pharmaceutical ingredient (API) is in short supply, it would be beneficial to reduce the number of experiments by predicting a suitable L/S ratio before starting the product development. The aim of the study was to decrease development time and the amount of API needed for the process development of high drug load formulations for continuous twin-screw wet granulation (TSWG). Mixer torque rheometry was used as a pre-formulation tool to predict the suitable L/S ratios for granulation experiments. Three different values that were based on the MTR curves, were determined and assessed for their ability to predict the suitable L/S ratio for TSWG. Three APIs (allopurinol, paracetamol and metformin HCl) were used as model substances in high drug load formulations containing 60% drug substance. The MCC-mannitol ratio was varied to assess the optimal composition for the high-dose formulations. The API solubility affected the mixer torque rheometer (MTR) curves and the optimum L/S ratio for TSWG. The highly soluble metformin needed a much lower L/S ratio compared with allopurinol and paracetamol. A design space was determined for each API based on granule flowability and tablet tensile strength. The flowability of the granules and tensile strength of the tablets improved with an increasing L/S ratio. The MCC-mannitol filler ratio had a significant effect on tabletability for paracetamol and metformin, and these APIs having poor compaction properties needed higher MCC ratios to achieve the 2 MPa limit. The MCC-mannitol ratio had no effect on the granule flow properties. Instead, API properties had the largest influence on both granule flow properties and tensile strength. Based on this study, both the L/S ratio and MCC-mannitol ratio are crucial in controlling the critical quality attributes in high drug load formulations processed by TSWG. The optimum flow and tablet mechanical properties were achieved when using 75:25 MCC-mannitol ratio. Both start of the slope and 2/3 of the L/S ratio at the maximum torque in MTR provided a solid guideline to aim for in a TSWG experiment. SN - 1879-0720 UR - https://www.unboundmedicine.com/medline/citation/35217210/Faster_to_First_time_in_Human:_Prediction_of_the_liquid_solid_ratio_for_continuous_wet_granulation_ DB - PRIME DP - Unbound Medicine ER -