Objective: The objective of this study was to develop a method that enabled granulation in a counter-rotating batch mixer to emulate large scale dry twin screw granulation trials. Methods: Four granulations were prepared using counter rotating batch mixing for formulations containing a mixture of different particle sizes of the API (70% w/w) and polymer (30% w/w). Milled theophylline (MTHF; fine API) was blended with coarse hydroxypropyl cellulose (HPC MF; coarse polymer), theophylline (THF; coarse API) with fine hydroxypropyl cellulose (HPC EXF, fine polymer), and the other two formulations consisted of both components in the blend being fine or coarse. Results: The formulations selected for granulation had the lowest friction coefficient, f, as a function of drug load determined by the iShear((R)) powder flow rheometer. Despite the non-uniform chaotic and random nature of thermal granulation, each formulation granulated reproducibly, though the evolution for each was different. Conclusion: This work highlighted that, firstly it is possible to measure plastic and frictional energy dissipation as product temperature. Secondly, granule growth and density were found to be proportional to the onset of polymer molecular mobility activated by the heat liberated from interparticle velocity differences via mechanical work (torque) required to move agglomerates through the mixer for the duration of each run.

A model was developed to describe the nitration of cellulose in mixed acids used in the production of military grade nitrocellulose. Acid dissociation, swelling, diffusion, and chemical reaction were considered to model the nitration of industrially important cellulose materials for given reaction times and conditions. This model is supported by experimental work conducted to measure the dynamics of swelling and diffusion in wood pulp slivers, and the model was validated using the results of lab-scale nitration reactions. Microcomputed tomography was also used to perform a structural analysis of wood pulp slivers that were cut on industrial, rotary cutting machines to evaluate features that may influence the reactivity of these materials.

A model has been developed to describe the reaction kinetics of single cellulose fibers (SCFs) in mixtures of nitric acid, sulfuric acid, and water during the production of highly nitrated nitrocellulose. Experiments were performed to provide insight into factors affecting the rate and extent of reaction for the nitration of wood-pulp-derived cellulose fibers in mixed acids and to provide kinetic data for model evaluation and kinetic parameter estimation. This work provided considerable information regarding the nature of the chemical reaction, and demonstrated that fiber properties do not play a significant role in the reaction kinetics or extent of reaction. This finding is particularly important because it allows for much broader range of wood pulps to be considered for industrial-scale nitration than have historically been used. A semiempirical kinetic model was developed to describe the conversion of cellulose to nitrocellulose as an equilibrium controlled reaction using these results. This kinetic model yielded excellent agreement with experimental results over the entire range of temperatures, fiber types, and reaction times studied.

The aims of this study were to assess the processing window of hypromellose acetate succinate (HPMCAS) as a polymeric carrier for hot-melt extrusion, and to investigate the effect of screw configuration and processing parameters on the physicochemical properties of HPMCAS extrudates. The processability was investigated using a Brabender® mixer and a Pharma 11 Twin Screw Extruder. HPMCAS extrudates were characterized with regard to glass transition temperature, true density, yellowness index, crystallinity, morphology, and free succinic acid/acetic acid/succinoyl group/acetyl group content. The specific energy input and mean residence time were also calculated and correlated to the physicochemical properties of final extrudates. Additionally, the effect of the die opening size of the twin screw extruder was investigated. The glass transition temperature of HPMCAS was found to be 137 and 133°C, using dynamic mechanical analyzer and oscillatory rheometer, respectively. HPMCAS demonstrated a shear thinning behavior at all temperatures tested (150, 160, and 170°C). The process conditions, screw configurations, as well as the diameter of die opening significantly affect the amount of free acetic acid and succinic acid. With a modified screw configuration and 1-mm die, the amounts of free acetic acid and succinic acid from the material processed at 180°C were 0.114% and 0.337%, respectively. Moreover, when the die was removed, the amounts of free acetic acid and succinic acid were further reduced to 0.084% and 0.294%, respectively. In conclusion, we successfully extruded HPMCAS at a temperature as low as 130°C and up to 180°C without any significant thermal degradation.

Nanoextrusion was used to produce extrudates of griseofulvin, a poorly water-soluble drug, with the objective of examining the impact of drug particle size and polymeric matrix type-size of the extrudates on drug dissolution enhancement. Hydroxypropyl cellulose (HPC) and Soluplus (R) were used to stabilize wet-milled drug suspensions and form matrices of the extrudates. The wet-milled suspensions along with additional polymer (HPC/Soluplus (R)) were fed, to a co-rotating twin-screw extruder, which dried the suspensions and formed various extrudates. The extrudates were dry-milled and sieved into samples with two different sizes. A wet-milled suspension was also spray-dried in comparison to nanoextrusion. Due to differences in polymer-drug miscibility, two forms of the drug were prepared: extrudates with nano/micro-crystalline drug particles dispersed in the HPC matrix as a secondary phase (nano/microcomposites) and extrudates with amorphous drug molecularly dispersed within the Soluplus matrix (amorphous solid dispersion, ASD). Under non-supersaturating conditions in the dissolution medium, drug nanocrystals in the HPC-based nanocomposites dissolved faster than the amorphous drug in Soluplus (R)-based ASD. While smaller extrudate particles led to faster drug release for the ASD, such matrix size effect was weaker for the nanocomposites. These findings suggest that nanocrystal-based formulations could outperform ASDs for fast dissolution of low-dose drugs. (C) 2017 Elsevier B.V. All rights reserved.

The dissolution rate of the active pharmaceutical ingredients in pharmaceutical hot-melt extrusion is the most critical elementary step during the extrusion of amorphous solid solutions - total dissolution has to be achieved within the short residence time in the extruder. Dissolution and dissolution rates are affected by process, material and equipment variables. In this work, we examine the effect of one of the material variables and one of the equipment variables, namely, the API particle size and extruder screw configuration on the API dissolution rate, in a co-rotating, twin-screw extruder. By rapidly removing the extruder screws from the barrel after achieving a steady state, we collected samples along the length of the extruder screws that were characterized by polarized optical microscopy (POM) and differential scanning calorimetry (DSC) to determine the amount of undissolved API. Analyses of samples indicate that reduction of particle size of the API and appropriate selection of screw design can markedly improve the dissolution rate of the API during extrusion. In addition, angle of repose measurements and light microscopy images show that the reduction of particle size of the API can improve the flowability of the physical mixture feed and the adhesiveness between its components, respectively, through dry coating of the polymer particles by the API particles. (C) 2014 Elsevier B.V. All rights reserved.

This chapter first presents and discusses the physical phenomena taking place in both injection molding machines and the molds, which enable the injection molding process to produce shaped thermoplastic polymer products reproducibly, inexpensively and rapidly, with only minimum industrial waste stream. Industrial waste generated aside, it then addresses the question of whether the existing injection molding processes and equipment are appropriate for producing tablets of active pharmaceutical ingredient (API) solid solutions in polymer excipients, where the total dissolution of the API in the molten excipient, and the absence of API process-generated degradation must be guaranteed. The arguments presented indicate the need for specific modifications of the existing injection molding processes, which change and improve the melting and laminar mixing generated, to assure API dissolution, and decrease the chances of API degradation originating from the process.

A simple, sensitive, efficient, and novel method analyzing the number of spherulitic nuclei was proposed to estimate the solubility of a model drug acetaminophen (APAP) in poly(ethylene oxide) (PEO). At high crystallization temperature (323 K), 10% APAP-PEO had the same low number of spherulitic nuclei as pure PEO, indicating that APAP and PEO were fully miscible. At low crystallization temperature (303 K), the number of nuclei for 10% APAP-PEO was significantly higher, suggesting that APAP was oversaturated and therefore recrystallized and acted as a nucleating agent. Based on the results obtained, the solubility of APAP in PEO is possibly between the concentration of 0.1% and 1% at 303 K. The spherulitic growth rate G of PEO was found to decrease with increasing APAP concentration, suggesting that APAP is most likely functioning as a chemical defect and is either rejected from or included in the PEO crystals during chain folding. APAP could possibly locate in the inter-spherulitic, inter-fibrillar, inter-lamellar, or intra-lamellar regions of PEO. At 323 K, the morphology of 10% APAP-PEO is more dendritic than spherulitic with large unfilled space in between dendrites and spherulites, which is a sign of one or the combination of the four modes of segregation. An extensive spherulitic nucleation and growth kinetics study using the classical theoretical relationships, for example, the Hoffman-Lauritzen (HL) and Avrami theories, was conducted. Both microscopic and differential scanning calorimetric (DSC) analysis yielded similar values for the nucleation constant Kg as well as the fold surface free energy σe and work of chain folding q. The values of σe and q increased with APAP concentration, indicating that the chain folding of PEO was hindered by APAP.

Solid dispersion technologies such as hot-melt extrusion and spray drying are often used to enhance the solubility of poorly soluble drugs. The biggest challenge associated with solid dispersion systems is that amorphous drugs may phase-separate from the polymeric matrix and recrystallize during storage. A more fundamental understanding of drug-polymer mixtures is needed for the industry to embrace the solid dispersion technologies. In this study, a theoretical model based on Flory–Huggins lattice theory was utilized to predict the solubility of a model drug acetaminophen (APAP) in a semi-crystalline polymer poly(ethylene oxide) (PEO) at 300 K. The interaction parameter χ was calculated to be −1.65 from the depression of drug’s melting temperature determined from rheological and differential scanning calorimetry analysis. The equilibrium solubility in amorphous PEO was estimated to be 11.7% at 300 K. Assuming no APAP molecules dissolve in the crystalline part of PEO, the adjusted theoretical solubility is around 2.3% considering PEO being 80% crystalline. The solubility of APAP in PEG 400 was calculated to be 14.6% by using the same χ value, close to the experimental measurement 17.1%. The drug’s solubility could be altered noticeably by the change of both χ and polymer molecular weight. The study also suggests that the depression of drug’s melting point is a good indicator for preliminary polymer screening. The polymer that reduces the melting point the most is likely to be most miscible with the drug.

In conjunction with UV technology, a fluid energy mill (FEM) was demonstrated to simultaneously and in-situ achieve several functions, namely: size reduction of pre-coated coarse micron-sized particles with UV-curable chemicals into smaller (ca. 1–10 μm) particles, coating of UV chemicals onto the milled particles, and curing of the UV chemicals. Potassium chloride (KCl) was chosen as the matrix material, and acrylate was chosen as the UV-curable formulation. The hold-up mass method was utilized to estimate the average residence time of particles in the FEM, the results of which showed that the average residence time decreases with increasing grinding pressure and solid feed rate, whereas it was not significantly affected by feeding pressure. Fluorescent microscopy showed that the UV-curable chemicals were evenly transferred to almost every single particle during FEM milling without UV irradiation, whereas they were transferred extensively, but to a lesser extent during FEM milling with UV irradiation. Thermal analysis (TGA and DSC) and IR analysis were employed to characterize the conversion of the free radical polymerization. IR analysis showed that the double bond conversion was up to 71%, denoting extensive curing.

The hot melt mixing (HMM) process was used to dissolve 30 wt% of a model drug, indomethacin (INM), in Soluplus (R) a water soluble polymer excipient. Comprehensive characterization of the HMM-prepared samples, using differential scanning calorimetry, X-ray diffraction, Fourier Transform Infrared spectroscopy, and optical microscopy, strongly suggests that INM was in amorphous state, forming a solid solution with the polymer. Furthermore, to understand the impact of foaming on INM's release profile, the HMM product was foamed in a batch process using supercritical carbon dioxide (CO2). Dissolution tests of HMM and reference samples were conducted in aqueous solutions with pH 7.4 and 1.2. In all cases INM's release showed strong pH-dependency; faster release and a greater amount of INM was released at pH 7.4 than at pH 1.2. For pure INM and the physical mixture, the drug's ionizable character results in the observed pH-dependency. While for the HMM samples it is also a consequence of theformation of hydrogen bonds between Soluplus (R) and INM which hinder polymer dissolution at pH 1.2. It was observed that the release rate of INM from different sample types at pH 7.4 decreased in the following sequence: foamed HMM > unfoamed HMM > crystalline INM > physical mixture. POLYM. ENG. SCI., 2012. (C) 2012 Society of Plastics Engineers

Hot Melt Extrusion (HME), a novel and potentially disruptive process for manufacturing oral dosage pharmaceutical products, has been explored and studied in recent times, by both industrial and academic investigators, because of its potential of rendering poorly water-soluble active pharmaceutical ingredients (APIs) readily bioavailable to patients through oral dosages. This article presents a brief review of HME from the "elementary steps of polymer processing" perspective: handling of particulate solids, melting, mixing, devolatilization and stripping, pressurization, pumping, as well as dissolution of the API in molten polymeric excipient processed stream. In contrast to traditional polymer processing, the dissolution of the API in the molten excipient during HME is the most important, key, elementary step. The main focus of this article is to discuss the physico-chemical and transport phenomena involved in dissolution and the material, equipment design, and HME process variables which affect it. The main task of the dissolution is to completely dissolve APIs in polymeric melt within the shortest possible residence time, without raising the processed stream melt temperature, and eliminating the possibility of degradation of heat sensitive APIs. We concluded from our work that the dissolution process is a laminar forced convective diffusion process. We will also present results on how to promote the dissolution rate through three categories of variables: process variables (screw speed, feeding rate, barrel temperature,), equipment variables (screw elements and configurations) and material variables (viscosity ratio, solubility parameters and particle sizes of API and excipient particulates). A novel viscometric method for the determination of the solubility of APIs in polymeric melts will also be discussed.

A novel simultaneous, in situ milling and coating method carried out in a fluid energy mill (FEM) is applied for the first time to prepare nanoparticle-coated CaCO3 (CC) additives for polymer composite materials. Simply milled (without coating) CC particles and as-received CC particles were used as references for comparison. The effects of the grinding pressure and the fraction of the nanoparticles on the size and flowability of CC particles were studied. The composites made with polypropylene (PP) and this specially prepared CC have higher elongation at break, elastic modulus, and impact strength, compared with the PP filled with uncoated CC. The thermal and thermo-oxidative stabilities of PP are improved as well by introducing the milled and nanoparticle-coated CC. POLYM. ENG. SCI., 2012. (C) 2011 Society of Plastics Engineers