Impact of polymeric excipient on cocrystal formation via hot-melt extrusion and subsequent downstream processing.

Pharmaceutical cocrystals have gained increasing interest due to their potential to modify the physicochemical properties of drugs. Herein, a 1:1 cocrystal of ibuprofen (IBU) as a BCS class II active pharmaceutical ingredient (API) and nicotinamide as coformer was produced using a hot-melt extrusion (HME) process. The effect of process parameters such as barrel temperature and screw speed were studied. It was shown that the addition of polymeric excipient such as soluplus (Sol) decreases the cocrystallization temperature by enhancing the interaction between API and coformer. In order to study the effect of cocrystallization on the tableting properties of IBU-NIC cocrystal, 5 different formulations of pure IBU, IBU-NIC cocrystal, IBU-NIC physical mixture, IBU-NIC-Sol physical mixture and IBU-NIC-Sol cocrystal were tableted by a compaction simulator. Tabletability, compactibility and compressibility were investigated. The sample with IBU-NIC-Sol cocrystal formulation outperformed all the other formulations in terms of tabletability, compactibility and compressibility. Interestingly, this sample was even superior to the IBU-NIC cocrystal sample which verified the advantageous effect of the presence of an excipient. Moreover, dissolution test confirmed a noticeable increase in the dissolution of not only the cocrystal samples but even the physical mixtures of IBU and NIC compared with pure IBU.

Karimi-Jafari M ，Ziaee A ，Iqbal J ，O'Reilly E ，Croker D ，Walker G ... -  《-》

Engineering of pharmaceutical cocrystals in an excipient matrix: Spray drying versus hot melt extrusion.

The comparison of spray drying versus hot melt extrusion (HME) in order to formulate amorphous solid dispersions has been widely studied. However, to the best of our knowledge, the use of both techniques to form cocrystals within a carrier excipient has not previously been compared. The combination of ibuprofen (IBU) and isonicotinamide (INA) in a 1:1 M ratio was used as a model cocrystal. A range of pharmaceutical excipients was selected for processing - mannitol, xylitol, Soluplus and PVP K15. The ratio of cocrystal components to excipient was altered to assess the ratios at which cocrystal formation occurs during spray drying and HME. Hansen Solubility Parameter (HSP) and the difference in HSP between the cocrystal and excipient (ΔHSP) was employed as a tool to predict cocrystal formation. During spray drying, when the difference in HSP between the cocrystal and the excipient was large, as in the case of mannitol (ΔHSP of 18.3 MPa0.5), a large amount of excipient (up to 50%) could be incorporated without altering the integrity of the cocrystal, whereas for Soluplus and PVP K15, where the ΔHSP was 2.1 and 1.6 MPa0.5 respectively, the IBU:INA cocrystal alone was only formed at a very low weight ratio of excipient, i.e. cocrystal:excipient 90:10. Remarkably different results were obtained in HME. In the case of Soluplus and PVP K15, a mixture of cocrystal with single components (IBU and INA) was obtained even when only 10% excipient was included. In conclusion, in order to reduce the number of unit operations required to produce a final pharmaceutical product, spray drying showed higher feasibility over HME to produce cocrystals within a carrier excipient.

Walsh D ，Serrano DR ，Worku ZA ，Madi AM ，O'Connell P ，Twamley B ，Healy AM ... -  《-》

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 ... -  《-》

Artificial neural networks (ANNs) and partial least squares (PLS) regression in the quantitative analysis of cocrystal formulations by Raman and ATR-FTIR spectroscopy.

The present work describes the development of an efficient, fast and accurate method for the quantification of polymer-based cocrystal formulations. Specifically, the content of carbamazepine-nicotinamide (CBZ/NIC) and ibuprofen-nicotinamide (IBU/NIC) cocrystals in Soluplus®-based formulations was independently determined with the aid of either Raman or Attenuated Total Reflectance Fourier-Transform Infrared Spectroscopy (ATR-FTIR) spectroscopy. Spectra peaks from mixtures of IBU/NIC and CBZ/NIC cocrystals with Soluplus at a ratio ranging from 90/10 to 1/99 w/w (cocrystal to SOL) were evaluated and modelled with the aid of feed-forward, back-propagation artificial neural networks (ANNs) and partial least squares (PLS) regression analysis. A 25 full-factorial experimental design was employed in order to evaluate the effect of ANN's structure (number of hidden units) and training (number of iteration cycles) parameters along with the effect of Raman or FTIR spectra region and data preprocessing (direct orthogonal signal correction - DOSC, second derivative, or no preprocessing) on ANN's fitting performance. Results showed that when DOSC preprocessing was employed excellent ANN fitting in both Raman (root mean squared error of prediction (RMSEp) values of 0.43 and 0.34 for IBU/NIC-SOL and CBZ/NIC-SOL, respectively) and FTIR (RMSEp values of 0.04 and 0.03 for IBU/NIC-SOL and CBZ/NIC-SOL, respectively) spectra was obtained. Comparison of ANNs fitting results with PLS regression (RMSEp for IBU/NIC-SOL was 0.94 and 7.36, and for CBZ/NIC-SOL 7.29 and 15.63, using Raman and FTIR analysis, respectively) revealed ANN's fitting superiority, which can be attributed to their inherent non-linear predictive ability.

Barmpalexis P ，Karagianni A ，Nikolakakis I ，Kachrimanis K ... -  《-》

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 《-》