Fernando Alvarez-Nunez

Manufacture of pharmaceutical co‐crystals using twin screw extrusion: A solvent‐less and scalable process

Pharmaceutical scientists are currently facing an increasing number of drug molecules with less than ideal properties such as poor solubility and lack of acceptable physical and chemical stability. Therefore, significant efforts in pharmaceutical sciences have concentrated on finding alternate solid forms and/or formulations with an aim of improving these properties. As part of these efforts, co-crystals have been identified as viable alternative solid forms, which in some instances may improve the drugability properties of a development candidate. Co-crystals have been defined as crystalline materials that comprise of two or more components that are solids at room temperature (in order to distinguish them from hydrates and solvates) held together by noncovalent forces. The distinction between a salt and a co-crystal lies in the fact that there is no proton transfer occurring between the constituents of a co-crystal. There has been an increased interest in cocrystals in the last few years and a number of publications have highlighted the beneficial properties of co-crystals. In order to be considered viable candidates for development, a scalable method to produce co-crystals must be established. Traditionally co-crystals have been prepared by grinding the constituents together.

Application of Twin Screw Extrusion in the Manufacture of Cocrystals, Part I: Four Case Studies

The application of twin screw extrusion (TSE) as a scalable and green process for the manufacture of cocrystals was investigated. Four model cocrystal forming systems, Caffeine-Oxalic acid, Nicotinamide-trans cinnamic acid, Carbamazepine-Saccharin, and Theophylline-Citric acid, were selected for the study. The parameters of the extrusion process that influenced cocrystal formation were examined. TSE was found to be an effective method to make cocrystals for all four systems studied. It was demonstrated that temperature and extent of mixing in the extruder were the primary process parameters that influenced extent of conversion to the cocrystal in neat TSE experiments. In addition to neat extrusion, liquid-assisted TSE was also demonstrated for the first time as a viable process for making cocrystals. Notably, the use of catalytic amount of benign solvents led to a lowering of processing temperatures required to form the cocrystal in the extruder. TSE should be considered as an efficient, scalable, and environmentally friendly process for the manufacture of cocrystals with little to no solvent requirements.

Manufacture and Performance Evaluation of a Stable Amorphous Complex of an Acidic Drug Molecule and Neusilin

In this paper, we explore the use of Neusilin, an inorganic magnesium aluminometasilicate, to stabilize the amorphous form of an acidic drug Sulindac. Both cryomilling and ball milling of the drug with Neusilin were found to produce the amorphous phase. However, the ball-milled (BM) material exhibited superior physical stability when compared with the cryomilled material at 40°C/75% relative humidity. (13) C solid-state nuclear magnetic resonance investigation of the BM material revealed an acid-base reaction between Sulindac and Neusilin. Optimal milling conditions and the kinetics of salt formation were also established. As benchtop milling is a laboratory-scale process, a scalable process was developed to make Sulindac-Neusilin amorphous drug complex using hot-melt extrusion (HME). The dissolution properties of the resulting HME material was found to have been improved over the material made by benchtop milling while maintaining similar physical stability. The HME material was used to make tablets using a direct compression method. The HME tablets were found to have better dissolution properties than tablets made from crystalline Sulindac. For the broad class of acidic drugs containing the carboxyl moiety, inorganic silicates such as Neusilin would offer a better choice than organic polymers to stabilize the amorphous phase.

Isothermal microcalorimetry to investigate the phase separation for amorphous solid dispersions of AMG 517 with HPMC-AS.

Understanding the crystallization kinetics of an amorphous drug is critical for the development of an amorphous solid dispersion (ASD) formulation. This paper examines the phase separation and crystallization of the drug AMG 517 in ASDs of varying drug load at various conditions of temperature and relative humidity using isothermal microcalorimetry. ASDs of AMG 517 in hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were manufactured using a Buchi 290 mini spray dryer system. ASDs were characterized using modulated differential scanning calorimetry (mDSC) and scanning electron microscopy (SEM) prior to isothermal microcalorimetry evaluation, and crystallinity was measured using (19)F solid state nuclear magnetic resonance spectroscopy (SSNMR), before and after crystallization. The crystallization of ASDs of AMG 517 in HPMC-AS was significantly slowed by the presence of HPMC-AS polymer, indicating enhanced physical stability for the ASD formulations. A two-phase crystallization was observed by isothermal microcalorimetry at temperatures near the glass transition temperature (Tg), indicating a drug-rich phase and a miscible ASD phase. (19)F SSNMR showed that only partial crystallization of the drug occurred for the ASDs, suggesting a third phase which did not crystallize, possibly representing a thermodynamically stable, soluble component. Isothermal microcalorimetry provides important kinetic data for monitoring crystallization of the drug in the ASDs and, together with (19)F SSNMR, suggests a three-phase ASD system for AMG 517 in HPMC-AS.

Enhancing and Sustaining AMG 009 Dissolution from a Bilayer Oral Solid Dosage Form via Microenvironmental pH Modulation and Supersaturation

Enhancing and sustaining AMG 009 dissolution from a matrix tablet via microenvironmental pH modulation and supersaturation, where poorly soluble acidic AMG 009 molecule was intimately mixed and compressed together with a basic pH modifier (e.g., sodium carbonate) and nucleation inhibitor hydroxypropyl methylcellulose K100 LV (HPMC K100 LV), was demonstrated previously. However, not all acidic or basic drugs are compatible with basic or acidic pH modifiers either chemically or physically. The objective of this study is to investigate whether similar dissolution enhancement of AMG 009 can be achieved from a bilayer dosage form, where AMG 009 and sodium carbonate are placed in a separate layer with or without the addition of HPMC K100 LV in each layer. Study results indicate that HPMC K100 LV-containing bilayer dosage forms gained similar dissolution enhancement as matrix dosage forms did. Bilayer dosage forms without HPMC K100 LV benefitted the least from dissolution enhancement.

Enhancing and Sustaining AMG 009 Dissolution from a Matrix Tablet Via Microenvironmental pH Modulation and Supersaturation

The objective of this study was to investigate the combined effect of pH modifiers and nucleation inhibitors on enhancing and sustaining the dissolution of AMG 009 tablet via supersaturation. Several bases and polymers were added as pH modifiers and nucleation inhibitors, respectively, to evaluate their impact on the dissolution of AMG 009 tablets. The results indicate that sodium carbonate, among the bases investigated, enhanced AMG 009 dissolution the most. HPMC E5 LV, among the nucleation inhibitors tested, was the most effective in sustaining AMG 009 supersaturation. The release of AMG 009 went from 4% for tablets which did not contain both sodium carbonate and HPMC E5 LV to 70% for the ones that did, resulting in a 17.5-fold increase in the extent of dissolution. The effect of compression force and disintegrant on the dissolution of tablets were also evaluated. The results indicate that compression force had no effect on AMG 009 release. The addition of disintegrating agents, on the other hand, decreased the dissolution of AMG 009.

Maximizing the Impact of Physiologically-Based Oral Absorption Modeling and Simulation.

The challenge of bringing innovative medicines to patients in combination with intense competition within the pharmaceutical industry has induced companies to develop quality medicines more efficiently and cost-effectively. State-of-the-art approaches to advance drug development have never been so urgent. One such approach that has been gaining traction within the industry is the application of modeling and simulation. In this commentary, the benefits of physiologically based oral absorption modeling and simulation in drug development are highlighted and suggestions for maximizing its impact are provided.

Manufacture of Pharmaceutically Relevant Materials by Mechanochemistry Using Twin Screw Extrusion

Mechanochemistry broadly refers to the class of chemical reactions that are induced by the application of mechanical force. In the context of pharmaceutical materials, mechanochemistry has been described in the literature for the preparation of cocrystals, salts, and amorphous complexes. In almost all these examples, laboratory-scale mills have been used to demonstrate the production of the aforementioned materials. While laboratory-scale mills demonstrate the utility of the mechanochemical concept, they typically produce small quantities of material and are not considered scalable processes. In this chapter, the application of twin-screw extrusion (TSE) in the production of cocrystals, salts, and amorphous complexes is described. Unlike other mechanical mixing procedures, TSE is a continuous process and lends itself to scalability. TSE can be considered an efficient, scalable, and environmentally friendly process for the consistent manufacture of pharmaceutically relevant systems.

Prediction of Air Entrapment in Tableting: An Approximate Solution

An approximate solution is presented for the prediction of air entrapment during tableting. Assuming weak coupling of the deformation of the solid phase, the flow of interstitial air and a set of reasonable additional geometric assumptions, the general problem is reduced to 1 dimension. Experimental values of air permeability through tablet specimens of commonly used pharmaceutical excipients were obtained using a 3D printed test cell outfitted to a powder rheometer. Using these values, combined with a numerical solution of the governing partial differential equation, parametric studies are presented that demonstrate the importance of permeability, compaction speed, tablet size, and punch-die tolerance on air entrapment. In addition, a first-order approximation of the role of entrapped air on the measured radial tensile strength of formed tablets is presented.