Mechanical Activation by Ball Milling As a Strategy to Prepare Highly Soluble Pharmaceutical Formulations in the Form of Co-Amorphous, Co-Crystals, or Polymorphs

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2022 Oct 27

PMID 36297439

Authors

Luz Maria Martinez

Jorge Cruz-Angeles

Monica Vazquez-Davila

Eduardo Martinez

Paulina Cabada

Columba Navarrete-Bernal

Flor Cortez

Affiliations

Soon will be listed here.

Abstract

Almost half of orally administered active pharmaceutical ingredients (APIs) have low solubility, which affects their bioavailability. In the last two decades, several alternatives have been proposed to modify the crystalline structure of APIs to improve their solubility; these strategies consist of inducing supramolecular structural changes in the active pharmaceutical ingredients, such as the amorphization and preparation of co-crystals or polymorphs. Since many APIs are thermosensitive, non-thermal emerging alternative techniques, such as mechanical activation by milling, have become increasingly common as a preparation method for drug formulations. This review summarizes the recent research in preparing pharmaceutical formulations (co-amorphous, co-crystals, and polymorphs) through ball milling to enhance the physicochemical properties of active pharmaceutical ingredients. This report includes detailed experimental milling conditions (instrumentation, temperature, time, solvent, etc.), as well as solubility, bioavailability, structural, and thermal stability data. The results and description of characterization techniques to determine the structural modifications resulting from transforming a pure crystalline API into a co-crystal, polymorph, or co-amorphous system are presented. Additionally, the characterization methodologies and results of intermolecular interactions induced by mechanical activation are discussed to explain the properties of the pharmaceutical formulations obtained after the ball milling process.

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References

Liu C, Liu Z, Chen Y, Chen Z, Chen H, Pui Y . Oral bioavailability enhancement of β-lapachone, a poorly soluble fast crystallizer, by cocrystal, amorphous solid dispersion, and crystalline solid dispersion. Eur J Pharm Biopharm. 2018; 124:73-81. DOI: 10.1016/j.ejpb.2017.12.016. View

Zhang X, Xing H, Zhao Y, Ma Z . Pharmaceutical Dispersion Techniques for Dissolution and Bioavailability Enhancement of Poorly Water-Soluble Drugs. Pharmaceutics. 2018; 10(3). PMC: 6161168. DOI: 10.3390/pharmaceutics10030074. View

Laitinen R, Lobmann K, Grohganz H, Strachan C, Rades T . Amino acids as co-amorphous excipients for simvastatin and glibenclamide: physical properties and stability. Mol Pharm. 2014; 11(7):2381-9. DOI: 10.1021/mp500107s. View

Zhu S, Gao H, Babu S, Garad S . Co-Amorphous Formation of High-Dose Zwitterionic Compounds with Amino Acids To Improve Solubility and Enable Parenteral Delivery. Mol Pharm. 2017; 15(1):97-107. DOI: 10.1021/acs.molpharmaceut.7b00738. View

Cruz-Cabeza A, Bernstein J . Conformational polymorphism. Chem Rev. 2013; 114(4):2170-91. DOI: 10.1021/cr400249d. View

Shaikh R, Shirazian S, Guerin S, Sheehan E, Thompson D, Walker G . Understanding solid-state processing of pharmaceutical cocrystals via milling: Role of tablet excipients. Int J Pharm. 2021; 601:120514. DOI: 10.1016/j.ijpharm.2021.120514. View

Berry D, Steed J . Pharmaceutical cocrystals, salts and multicomponent systems; intermolecular interactions and property based design. Adv Drug Deliv Rev. 2017; 117:3-24. DOI: 10.1016/j.addr.2017.03.003. View

Martinez-Jimenez C, Cruz-Angeles J, Videa M, Martinez L . Co-Amorphous Simvastatin-Nifedipine with Enhanced Solubility for Possible Use in Combination Therapy of Hypertension and Hypercholesterolemia. Molecules. 2018; 23(9). PMC: 6225140. DOI: 10.3390/molecules23092161. View

Vasilev N, Surov A, Voronin A, Drozd K, Perlovich G . Novel cocrystals of itraconazole: Insights from phase diagrams, formation thermodynamics and solubility. Int J Pharm. 2021; 599:120441. DOI: 10.1016/j.ijpharm.2021.120441. View

10.

Mizoguchi R, Waraya H, Hirakura Y . Application of Co-Amorphous Technology for Improving the Physicochemical Properties of Amorphous Formulations. Mol Pharm. 2019; 16(5):2142-2152. DOI: 10.1021/acs.molpharmaceut.9b00105. View

11.

Slamova M, Prausova K, Epikaridisova J, Brokesova J, Kuentz M, Patera J . Effect of co-milling on dissolution rate of poorly soluble drugs. Int J Pharm. 2021; 597:120312. DOI: 10.1016/j.ijpharm.2021.120312. View

12.

Wu X, Wang Y, Xue J, Liu J, Qin J, Hong Z . Solid phase drug-drug pharmaceutical co-crystal formed between pyrazinamide and diflunisal: Structural characterization based on terahertz/Raman spectroscopy combining with DFT calculation. Spectrochim Acta A Mol Biomol Spectrosc. 2020; 234:118265. DOI: 10.1016/j.saa.2020.118265. View

13.

Mullers K, Paisana M, Wahl M . Simultaneous formation and micronization of pharmaceutical cocrystals by rapid expansion of supercritical solutions (RESS). Pharm Res. 2014; 32(2):702-13. DOI: 10.1007/s11095-014-1498-9. View

14.

Takagi T, Ramachandran C, Bermejo M, Yamashita S, Yu L, Amidon G . A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan. Mol Pharm. 2006; 3(6):631-43. DOI: 10.1021/mp0600182. View

15.

Lobmann K, Laitinen R, Strachan C, Rades T, Grohganz H . Amino acids as co-amorphous stabilizers for poorly water-soluble drugs--Part 2: molecular interactions. Eur J Pharm Biopharm. 2013; 85(3 Pt B):882-8. DOI: 10.1016/j.ejpb.2013.03.026. View

16.

Wu W, Grohganz H, Rades T, Lobmann K . Comparison of co-former performance in co-amorphous formulations: Single amino acids, amino acid physical mixtures, amino acid salts and dipeptides as co-formers. Eur J Pharm Sci. 2020; 156:105582. DOI: 10.1016/j.ejps.2020.105582. View

17.

Lobmann K, Laitinen R, Grohganz H, Gordon K, Strachan C, Rades T . Coamorphous drug systems: enhanced physical stability and dissolution rate of indomethacin and naproxen. Mol Pharm. 2011; 8(5):1919-28. DOI: 10.1021/mp2002973. View

18.

Kasten G, Lobo L, Dengale S, Grohganz H, Rades T, Lobmann K . In vitro and in vivo comparison between crystalline and co-amorphous salts of naproxen-arginine. Eur J Pharm Biopharm. 2018; 132:192-199. DOI: 10.1016/j.ejpb.2018.09.024. View

19.

Badal Tejedor M, Nordgren N, Schuleit M, Pazesh S, Alderborn G, Millqvist-Fureby A . Determination of Interfacial Amorphicity in Functional Powders. Langmuir. 2017; 33(4):920-926. DOI: 10.1021/acs.langmuir.6b03969. View

20.

Trask A, Shan N, Motherwell W, Jones W, Feng S, Tan R . Selective polymorph transformation via solvent-drop grinding. Chem Commun (Camb). 2005; (7):880-2. DOI: 10.1039/b416980h. View