title: Matrix-assisted cocrystallization (MAC) simultaneous production and formulation of pharmaceutical cocrystals by hot-melt extrusion.
abstract: A novel method for the simultaneous production and formulation of pharmaceutical cocrystals, matrix-assisted cocrystallization (MAC), is presented. Hot-melt extrusion (HME) is used to create cocrystals by coprocessing the drug and coformer in the presence of a matrix material. Carbamazepine (CBZ), nicotinamide (NCT), and Soluplus were used as a model drug, coformer, and matrix, respectively. The MAC product containing 80:20 (w/w) cocrystal:matrix was characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffraction. A partial least squares (PLS) regression model was developed for quantifying the efficiency of cocrystal formation. The MAC product was estimated to be 78% (w/w) cocrystal (theoretical 80%), with approximately 0.3% mixture of free (unreacted) CBZ and NCT, and 21.6% Soluplus (theoretical 20%) with the PLS model. A physical mixture (PM) of a reference cocrystal (RCC), prepared by precipitation from solution, and Soluplus resulted in faster dissolution relative to the pure RCC. However, the MAC product with the exact same composition resulted in considerably faster dissolution and higher maximum concentration (∼five-fold) than those of the PM. The MAC product consists of high-quality cocrystals embedded in a matrix. The processing aspect of MAC plays a major role on the faster dissolution observed. The MAC approach offers a scalable process, suitable for the continuous manufacturing and formulation of pharmaceutical cocrystals.
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana.
authors.forename: Kevin
authors.initials: K
authors.lastname: Boksa
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana.
authors.forename: Andrew
authors.initials: A
authors.lastname: Otte
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana. Electronic address: rpinal@purdue.edu.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Pinal
mesh_terms: D002152:Calorimetry, Differential Scanning / Q000379:methods; D002220:Carbamazepine / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D004355:Drug Stability; D006358:Hot Temperature; D009536:Niacinamide / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011145:Polyvinyls / Q000737:chemistry*; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D011145:Polyvinyls; C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; D009536:Niacinamide; D002220:Carbamazepine; D011092:Polyethylene Glycols
keywords: cocrystals; continuous manufacturing; crystal engineering; crystallization; dissolution; extrusion; formulation; matrix; polymers; solid dispersions; supersaturation