The role of the polymer matrix in solvent-free hot melt extrusion continuous process for mechanochemical synthesis of pharmaceutical cocrystal.

Solid-state synthesis of pharmaceutical cocrystals is of contemporary interest as it offers an efficient way to modify the physicochemical properties of Active Pharmaceutical Ingredient (API) including its melting point, solubility, compressibility or physical stability, without compromising its structural integrity and bioactivity. Therefore, research of novel and emerging techniques for solvent-free, continuous and scalable methods for cocrystal formation is of paramount importance for further industrial development. In this work we form a basis for knowledge-based synthesis and formulation of model pharmaceutical cocrystal (flufenamic acid, FFA: nicotinamide, NA; 1:1) via matrix-assisted cocrystallisation (MAC) using Hot Melt Extrusion (HME). Five different polymers frequently used in pharmaceutical drug delivery: Poloxamer P407 (PXM), PEG-PVA copolymer, Soluplus® (SOL), PVPVA64 and HPMCAS with different structural features and physicochemical properties were investigated as functional matrices for FFA:NA cocrystal synthesis via HME. Significant decrease of the torque value during MAC process was observed for all investigated polymers as compared to extrusion of neat FFA:NA cocrystal. The FFA:NA cocrystal encapsulated in the polymer matrix was successfully formed using semicrystalline PXM and PEG-PVA polymers at all investigated FFA:NA/polymer ratios. The use of amorphous polymers (SOL, PVPVA64, HPMCAS) as a cocrystallisation matrix resulted in formation of FFA:NA cocrystal embedded in an amorphous FFA:NA/polymer matrix (at polymer contents of 10 and 20 wt.%) or FFA:NA/polymer amorphous composites at SOL and PVPVA64 content of 30 wt.%. Furthermore, the significant increase of FFA dissolution was observed for FFA:NA cocrystal encapsulated in PXM and PEG-PVA matrices as compared to neat FFA form I. FFA form III and FFA:NA cocrystal. The presented work enables for the first time knowledge-based approach for simultaneous synthesis and formulation of pharmaceutical cocrystals via Hot Melt Extrusion a solvent-free, scalable and continuous process.

Gajda M ，Nartowski KP ，Pluta J ，Karolewicz B ... -  《-》

Tuning the cocrystal yield in matrix-assisted cocrystallisation via hot melt extrusion: A case of theophylline-nicotinamide cocrystal.

Polymer-assisted cocrystallisation via hot melt extrusion (HME) facilitates the cocrystallisation process and increases cocrystal yield compared with the HME of neat cocrystal components. This makes it an attractive method for the single-step continuous synthesis of pharmaceutical cocrystals. The aim of this study is to understand the effect of semicrystalline (Poloxamer P407, PXM) or amorphous (Soluplus®, SOL) polymers on the cocrystallisation of model theophylline-nicotinamide (TP:NA, 1:1) cocrystal with significantly different melting temperatures of API (TP, m.p. = 271.4 °C) and coformer (NA, m.p. = 128.7 °C) in neat and matrix-assisted cocrystallisation via HME. Compared with the processing of neat cocrystal components, the addition of PXM led to formulation of TP:NA cocrystal embedded in the polymer matrix and increased the cocrystal formation efficiency. On the other hand, the co-processing of cocrystal components with SOL resulted in the formation of cocrystal embedded in the amorphous polymer matrix or in the partially amorphous TP:NA/SOL composites. The one-step formulation of API:coformer mixtures with polymers using HME may result in phase changes or the formation of amorphous solid dispersions, which highlights the importance of matrix selection and phase control of the final product.

Gajda M ，Nartowski KP ，Pluta J ，Karolewicz B ... -  《-》

Continuous, one-step synthesis of pharmaceutical cocrystals via hot melt extrusion from neat to matrix-assisted processing - State of the art.

Use of hot melt extrusion (HME) as continuous manufacturing process in the cocrystal synthesis is of increasing interest from both industrial and academic perspective and it is seen as a newly developing branch of mechanochemistry with possible broad application in single step synthesis and formulation of pharmaceutical cocrystals. Furthermore, one-step formulation of pharmaceutical products results in combined processing of pharmaceutical cocrystal mixtures with polymers using HME, which may result in phase change or formation of amorphous solid dispersions during the material processing. The manuscript aims at providing selection guidelines and understanding of processing parameters and instrumental setup of importance to design the HME process for cocrystal synthesis. Furthermore, importance of stoichiometry control of the final product and the matrix selection criteria in simultaneous synthesis and formulation of pharmaceutical cocrystals via HME are provided. The first part of this review, introduce mechanochemical methods of cocrystals synthesis along brief explanation of the possible molecular mechanisms of cocrystal synthesis via mechanochemical approach. Subsequently, the critical process parameters i.e. temperature, screw speed, screw configuration or material feed rate of importance in successful synthesis of high quality product are described followed by literature examples of the processing of neat cocrystal compounds or matrix assisted cocrystallisation.

Gajda M ，Nartowski KP ，Pluta J ，Karolewicz B ... -  《-》

Matrix-assisted cocrystallization (MAC) simultaneous production and formulation of pharmaceutical cocrystals by hot-melt extrusion.

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.

Boksa K ，Otte A ，Pinal R 《-》

Understanding the Effects of a Polymer on the Surface Dissolution of Pharmaceutical Cocrystals Using Combined Experimental and Molecular Dynamics Simulation Approaches.

Kirubakaran P ，Wang K ，Rosbottom I ，Cross RBM ，Li M ... -  《-》