The choice of method for drug amorphization depends on various factors, including the physicochemical properties of the active pharmaceutical ingredients, the desired formulation, and scalability requirements. It is often important to consider a combination of methods or the use of excipients to further enhance the stability and performance of the amorphous drug. This study presents a comparison of techniques including melt quench, hot melt extrusion, solvent evaporation, ball milling, and lyophilization used for the preparation of amorphous ibrutinib. The amorphous material was thoroughly investigated using numerous techniques to examine changes in the physicochemical properties, stability, and degradation pathways of the drug product. During the examination, the temperature was discovered to be a key parameter for controlling the solubility and permeability of ibrutinib, which is influenced by the presence of the degradation product. We found that this degradation product could potentially polymerize and increase the molecular weight. The quantity, polymerization rate, and structure of the impurity can be regulated by the temperature variation during the amorphization processes. Additionally, the molecular weight of the degradation product was determined using Zimm plot analysis, which appeared for the first time in the literature for molecules of this category.

Department of Chemical Engineering University of Chemistry and Technology Technická 3 Prague 6 Dejvice 166 28 Czech Republic

Zentiva k s U Kabelovny 130 Prague 10 102 00 Czech Republic

See more in PubMed

Woyach J. A.; Johnson A. J.; Byrd J. C. The B-Cell Receptor Signaling Pathway as a Therapeutic Target in CLL. Blood 2012, 120, 1175–1184. 10.1182/blood-2012-02-362624. PubMed DOI PMC

Rauf F.; Festa F.; Park J. G.; Magee M.; Eaton S.; Rinaldi C.; Betanzos C. M.; Gonzalez-Malerva L.; LaBaer J. Ibrutinib Inhibition of ERBB4 Reduces Cell Growth in a WNT5A-Dependent Manner. Oncogene 2018, 37, 2237–2250. 10.1038/s41388-017-0079-x. PubMed DOI PMC

Advani R. H.; Buggy J. J.; Sharman J. P.; Smith S. M.; Boyd T. E.; Grant B.; Kolibaba K. S.; Furman R. R.; Rodriguez S.; Chang B. Y.; Sukbuntherng J.; Izumi R.; Hamdy A.; Hedrick E.; Fowler N. H. Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies. J. Clin. Oncol. 2013, 31, 88–94. 10.1200/JCO.2012.42.7906. PubMed DOI PMC

Barrientos J.; Rai K. Ibrutinib: a Novel Bruton’s Tyrosine Kinase Inhibitor with Outstanding Responses in Patients with Chronic Lymphocytic Leukemia. Leuk. Lymphoma 2013, 54, 1817–1820. 10.3109/10428194.2013.796049. PubMed DOI

Davids M. S.; Brown J. R. Ibrutinib: a First in Class Covalent Inhibitor of Bruton’s Tyrosine Kinase. Future Oncol. 2014, 10, 957–967. 10.2217/fon.14.51. PubMed DOI PMC

Haura E. B.; Rix U. Deploying Ibrutinib to Lung Cancer: Another Step in the Quest Towards Drug Repurposing. J. Natl. Cancer Inst. 2014, 106, dju250.10.1093/jnci/dju250. PubMed DOI PMC

Berglöf A.; Hamasy A.; Meinke S.; Palma M.; Krstic A.; Månsson R.; Kimby E.; Österborg A.; Smith C. I. E. Targets for Ibrutinib Beyond B Cell Malignancies. Scand. J. Immunol. 2015, 82, 208–217. 10.1111/sji.12333. PubMed DOI PMC

Cohen M. S.; Zhang C.; Shokat K. M.; Taunton J. Structural Bioinformatics-Based Design of Selective, Irreversible Kinase Inhibitors. Science 2005, 308, 1318–1321. 10.1126/science1108367. PubMed DOI PMC

Leproult E.; Barluenga S.; Moras D.; Wurtz J.-M.; Winssinger N. Cysteine Mapping in Conformationally Distinct Kinase Nucleotide Binding Sites: Application to the Design of Selective Covalent Inhibitors. J. Med. Chem. 2011, 54, 1347–1355. 10.1021/jm101396q. PubMed DOI

Dobrovolsky D.; Wang E. S.; Morrow S.; Leahy C.; Faust T.; Nowak R. P.; Donovan K. A.; Yang G.; Li Z.; Fischer E. S.; Treon S. P.; Weinstock D. M.; Gray N. S. Bruton Tyrosine Kinase Degradation as a Therapeutic Strategy for Cancer. Blood 2019, 133, 952–961. 10.1182/blood-2018-07-862953. PubMed DOI PMC

Zvoníček V.; Skořepová E.; Dušek M.; Babor M.; Žvátora P.; Šoóš M. First Crystal Structures of Pharmaceutical Ibrutinib: Systematic Solvate Screening and Characterization. Cryst. Growth Des. 2017, 17, 3116–3127. 10.1021/acs.cgd.7b00047. DOI

Serajuddin A. T. M. Salt Formation to Improve Drug Solubility. Adv. Drug Delivery Rev. 2007, 59, 603–616. 10.1016/j.addr.2007.05.010. PubMed DOI

Kostewicz E. S.; Wunderlich M.; Brauns U.; Becker R.; Bock T.; Dressman J. B. Predicting the Precipitation of Poorly Soluble Weak Bases upon Entry in the Small Intestine. J. Pharm. Pharmacol. 2004, 56, 43–51. 10.1211/0022357022511. PubMed DOI

de Jésus Ngoma P.; Kabamba B.; Dahlqvist G.; Sempoux C.; Lanthier N.; Shindano T.; Van Den Neste E.; Horsmans Y. Occult HBV Reactivation Induced by Ibrutinib Treatment: a Case Report. Acta Gastroenterol. Belg. 2015, 78, 424–426. PubMed

Shakeel F.; Salem-Bekhit M. M.; Iqbal M.; Haq N. Solubility and Thermodynamic Function of a New Anticancer Drug Ibrutinib in 2-(2-ethoxyethoxy)Ethanol+Water Mixtures at Different Temperatures. J. Chem. Thermodyn. 2015, 89, 159–163. 10.1016/j.jct.2015.04.014. DOI

Jirát J.; Rohlíček J.; Kaminský J.; Jirkal T.; Ridvan L.; Skořepová E.; Zvoníček V.; Dušek M.; Šoóš M. Formation of Ibrutinib Solvates: so Similar, Yet so Different. IUCrJ 2023, 10, 210–219. 10.1107/s2052252523001197. PubMed DOI PMC

Sebastian Rabe M. E.; Albrecht W.. Acid addition salt of ibrutinib. WO 2016050422 A1, 2015.

Rangaraj N.; Pailla S. R.; Chowta P.; Sampathi S. Fabrication of Ibrutinib Nanosuspension by Quality by Design Approach: Intended for Enhanced Oral Bioavailability and Diminished Fast Fed Variability. AAPS PharmSciTech 2019, 20, 326.10.1208/s12249-019-1524-7. PubMed DOI

Shi X.; Fan B.; Zhou X.; Chen Q.; Shen S.; Xing X.; Deng Y. Preparation and Characterization of Ibrutinib Amorphous Solid Dispersions: a Discussion of Interaction Force. J. Pharm. Innov. 2022, 17, 1074–1083. 10.1007/s12247-021-09585-y. DOI

Zvoníček V.; Skořepová E.; Dušek M.; Žvátora P.; Šoóš M. Ibrutinib Polymorphs: Crystallographic Study. Cryst. Growth Des. 2018, 18, 1315–1326. 10.1021/acs.cgd.7b00923. DOI

Kawakami K.; Pikal M. J. Calorimetric Investigation of the Structural Relaxation of Amorphous Materials: Evaluating Validity of the Methodologies. J. Pharm. Sci. 2005, 94, 948–965. 10.1002/jps.20298. PubMed DOI

Broadhead J.; Edmond Rouan S. K.; Rhodes C. T. The Spray Drying of Pharmaceuticals. Drug Dev. Ind. Pharm. 1992, 18, 1169–1206. 10.3109/03639049209046327. DOI

Ghebre-Sellassie I.; Ghebre-Selassie I.; Martin C. E.; Zhang F.; DiNunzio J.; Martin C.. Pharmaceutical Extrusion Technology; CRC Press, 2003.

Machiste E. O.; Giunchedi P.; Setti M.; Conte U. Characterization of Carbamazepine in Systems Containing a Dissolution Rate Enhancer. Int. J. Pharm. 1995, 126, 65–72. 10.1016/0378-5173(95)04085-4. DOI

Seefeldt K.; Miller J.; Alvarez-Núñez F.; Rodríguez-Hornedo N. Crystallization of Carbamazepine-Nicotinamide Cocrystal from the Amorphous Phase. AAPS J. 2004, 6, R6172. PubMed

Mullin J. W.Crystallization; Elsevier, 2001.

Pikal M. J.Freeze-Drying of Proteins: Process, Formulation, and Stability. Formulation and Delivery of Proteins and Peptides; ACS Publications, 1994; pp 120–133.

Moseson D. E.; Eren A.; Altman K. J.; Corum I. D.; Li M.; Su Y.; Nagy Z. K.; Taylor L. S. Optimization of Amorphization Kinetics during Hot Melt Extrusion by Particle Engineering: An Experimental and Computational Study. Cryst. Growth Des. 2022, 22, 821–841. 10.1021/acs.cgd.1c01306. DOI

Rahman N.; Azmi S. N. H.; Wu H.-F. The Importance of Impurity Analysis in Pharmaceutical Products: an Integrated Approach. Accredit. Qual. Assur. 2006, 11, 69–74. 10.1007/s00769-006-0095-y. DOI

Haser A.; Huang S.; Listro T.; White D.; Zhang F. An Approach for Chemical Stability during Melt Extrusion of a Drug Substance with a High Melting Point. Int. J. Pharm. 2017, 524, 55–64. 10.1016/j.ijpharm.2017.03.070. PubMed DOI

Vajjha S.; Bommuluri V.; Mohan P K. V. K.; Rumalla C. S.; Doddipalla R.; Kaliyaperumal M.; Korupolu R. B. Degradation Studies of Ibrutinib Under Stress Conditions: Characterisation and Structural Elucidation of Novel Degradants. J. Pharm. Biomed. Anal. 2019, 172, 9–17. 10.1016/j.jpba.2019.04.010. PubMed DOI

Konduru N.; Gundla R.; Katari N. K.; Paidikondala K.; Reddy A. S.; Jagadabi V. Development and Validation of a Stability-indicating Method for Ibrutinib: Identification and Separation of Degradation Products, Known and Genotoxic Impurities Using RP-HPLC/PDA and QDa Mass Detectors. Anal. Chem. Lett. 2020, 10, 113–136. 10.1080/22297928.2019.1673814. DOI

Mehta L.; Naved T.; Grover P.; Bhardwaj M.; Mukherjee D. LC and LC–MS/MS Studies for Identification and Characterization of New Degradation Products of Ibrutinib and Elucidation of Their Degradation Pathway. J. Pharm. Biomed. Anal. 2021, 194, 113768.10.1016/j.jpba.2020.113768. PubMed DOI

Goethals E. J.; Schacht E. H.; Bogaert Y. E.; Ali S. I.; Tezuka Y. The Polymerization of Azetidines and Azetidine Derivatives. Polym. J. 1980, 12, 571–581. 10.1295/polymj.12.571. DOI

Larsen C.; Bundgaard H. Polymerization of Penicillins: V. Separation, Identification and Quantitative Determination of Antigenic Polymerization Products in Ampicillin Sodium Preparations by High-Performance Liquid Chromatography. J. Chromatogr. A 1978, 147, 143–150. 10.1016/S0021-9673(00)85126-2. DOI

Yu L. X.; Amidon G. L.; Polli J. E.; Zhao H.; Mehta M. U.; Conner D. P.; Shah V. P.; Lesko L. J.; Chen M.-L.; Lee V. H. L.; Hussain A. S. Biopharmaceutics Classification System: The Scientific Basis for Biowaiver Extensions. Pharm. Res. 2002, 19, 921–925. 10.1023/A:1016473601633. PubMed DOI

Mark S.; Erick G.; David W.; Norbert P.. Crystalline Forms of a Bruton’s Tyrosine Kinase Inhibitor. US Patent 10,294,232 B2, 2012.

Crank J.; Crank E. P. J.The Mathematics of Diffusion; Clarendon Press, 1979.

Donbrow M.; Friedman M. Enhancement of Permeability of Ethyl Cellulose Films for Drug Penetration. J. Pharm. Pharmacol. 1975, 27, 633–646. 10.1111/j.2042-7158.1975.tb09525.x. PubMed DOI

Trunov D.; Francisco Wilson J.; Ježková M.; Šrom O.; Beranek J.; Dammer O.; Šoóš M. Monitoring of Particle Sizes Distribution during Valsartan Precipitation in the Presence of Nonionic Surfactant. Int. J. Pharm. 2021, 600, 120515.10.1016/j.ijpharm.2021.120515. PubMed DOI

Zemb T.; Lindner P., Neutron, X-rays and Light. Scattering Methods Applied to Soft Condensed Matter; Elsevier: North Holland, 2002.

Berne B. J.; Pecora R.Dynamic Light Scattering: With Applications to Chemistry, Biology, and Physics; Courier Corporation, 2000.

Stocco A.; Drenckhan W.; Rio E.; Langevin D.; Binks B. P. Particle-Stabilised Foams: an Interfacial Study. Soft Matter 2009, 5, 2215–2222. 10.1039/b901180c. DOI

Chen Z.; Zhai J.; Liu X.; Mao S.; Zhang L.; Rohani S.; Lu J. Solubility Measurement and Correlation of the Form A of Ibrutinib in Organic Solvents from 278.15 to 323.15K. J. Chem. Thermodyn. 2016, 103, 342–348. 10.1016/j.jct.2016.08.034. DOI

Tobyn M.; Brown J.; Dennis A. B.; Fakes M.; gao Q.; Gamble J.; Khimyak Y. Z.; McGeorge G.; Patel C.; Sinclair W.; Timmins P.; Yin S. Amorphous Drug-PVP Dispersions: Application of Theoretical, Thermal and Spectroscopic Analytical Techniques to the Study of a Molecule With Intermolecular Bonds in Both the Crystalline and Pure Amorphous State. J. Pharm. Sci. 2009, 98, 3456–3468. 10.1002/jps.21738. PubMed DOI

Zhu W.; Li C.; Zhang D.; Guan G.; Xiao Y.; Zheng L. Thermal Degradation Mechanism of Poly(butylene carbonate). Polym. Degrad. Stab. 2012, 97, 1589–1595. 10.1016/j.polymdegradstab.2012.06.029. DOI

Fang Y.; Jiang M.; Zhang W.; Sun K.; Chen X.. Synthesis method of ibrutinib. CN 107674079 B, 2019.