title: High-shear granulation as a manufacturing method for cocrystal granules.
abstract: Cocrystal formation allows the tailoring of physicochemical as well as of mechanical properties of an API. However, there is a lack of large-scale manufacturing methods of cocrystals. Therefore, the objective of this work was to examine the suitability of high-shear wet granulation as a manufacturing method for cocrystal granules on a batch scale. Furthermore, the cocrystal granules were characterized regarding their mechanical properties as well as their dissolution behavior. High-shear wet granulation was found to be a feasible manufacturing method for cocrystal granules. Cocrystal formation depended on the exposure time of the solids to the granulation liquid (water), the amount of liquid, the impeller speed of the granulator, and on the excipients (hydroxyl propylcellulose, microcrystalline cellulose, calcium hydrogenphosphate) used in the formulation. Storage stability was strongly influenced by the excipients, since in presence of calcium hydrogenphosphate, the poorly water-soluble salt calcium tartrate monohydrate was formed at high relative humidity. Interestingly, compactability was increased by cocrystal formation compared to that of the reference granules (piracetam and the respective excipients). The drug release was slightly decreased by cocrystal formation, most likely due to the lower solubility of the cocrystal. In the presence of calcium hydrogenphosphate however, no influence of cocrystal formation on either compactability or on drug release were observed, compared with the reference tablets. It was concluded that high-shear wet granulation is a valuable, however complex, manufacturing method for cocrystals. Cocrystal formation may influence compactability and drug release and thus affect drug performance and should be investigated during pre-formulation.
authors.affiliation: Dept. of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Dept. of Chemistry, University of Hamburg, Hamburg, Germany.
authors.forename: Sönke
authors.initials: S
authors.lastname: Rehder
authors.forename: Niels Peter Aae
authors.initials: NP
authors.lastname: Christensen
authors.forename: Jukka
authors.initials: J
authors.lastname: Rantanen
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Leopold
mesh_terms: D003460:Crystallization; D016503:Drug Delivery Systems; D005079:Excipients / Q000737:chemistry; D010316:Particle Size; D010889:Piracetam / Q000737:chemistry; D013059:Spectrum Analysis, Raman; D013314:Stress, Mechanical; D013607:Tablets / Q000737:chemistry*; D013644:Tartrates / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods*; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D005079:Excipients; D013607:Tablets; D013644:Tartrates; D014867:Water; C029768:tartaric acid; D010889:Piracetam
keywords: Cocrystal; Compactability; Drug release; High-shear granulation; Piracetam; Tartaric acid