Effects of Processing on a Sustained Release Formulation Prepared by Twin-Screw Dry Granulation.

Dry granulation is an indispensable process used to improve the flow property of moisture-sensitive materials. Considering the limitations of currently available dry granulation techniques, it is necessary to develop a novel technique. In this study, a twin-screw dry granulation (TSDG) technology was successfully applied to produce a sustained-release dry granule formulation, which was subsequently compressed into sustained-release tablets. Based on a preliminary study, theophylline was selected as model drug, Klucel™ EF, Ethocel™, and magnesium stearate were selected as excipients. A Resolution V Irregular Fraction Design was applied to determine the effect of different processing parameters (screw speed, feeding rate, barrel temperature, and screw configuration) on product properties (flow properties, particle size distribution, and dissolution time). A reliable model was achieved by combining the data obtained, and processing parameters were automatically optimized to attain the setting goal. In general, TSDG was demonstrated to be an alternative method for the preparation of dry granules. The continuous processing nature, simplicity of operation, and ease of optimization made TSDG competitive compared with other conventional dry granulation techniques.

Exploratory studies in heat-assisted continuous twin-screw dry granulation: A novel alternative technique to conventional dry granulation.

Dry granulation is the preferred technique for solvent-sensitive products, especially drugs with stability problems such as hydrolysis. Twin-screw granulation is a continuous granulation technique, offering a potential alternative to conventional dry granulation techniques such as roller compaction. The major advantage of twin-screw granulation is the ability to adjust process parameters of dry granulation without compromising the compression properties. This study was aimed to perform exploratory studies of heat-assisted continuous twin-screw dry granulation process to formulate sustained release tablets for APIs with different melting points: theophylline, acetaminophen and lidocaine hydrochloride hydrate. Granulation feasibility was studied with different binders (e.g. Klucel™ EF, Kollidon® VA64), sustained release agents (e.g. Klucel™ MF, Eudragit® RSPO) and diluents at various drug loads. The processing conditions were below the melting point or glass transition temperature of the formulation ingredients. After successful granulation, DSC and XRD studies revealed the crystalline nature of the granules and FTIR studies showed no interaction of the API with the excipients. The granules were compressed into sustained release tablets without any compressibility issues. The tablets were stable after testing for 6 months at 25 °C/60% RH. This novel continuous dry granulation technique may offer an excellent alternative to conventional dry granulation techniques.

Hydroxypropyl methylcellulose-based controlled release dosage by melt extrusion and 3D printing: Structure and drug release correlation.

The objective of this study was to develop a new approach for fabrication of zero order release of active pharmaceutical ingredients (APIs) using hot-melt extrusion (HME) and 3D printing technology to generate tablets with specific 3D structures. By correlating the geometry of the 3D printed tablets with their dissolution and drug release rates, mathematical models that have been developed to describe drug release mechanisms were also studied. Acetaminophen was used as a model drug, and Benecel™ hydroxypropyl methylcellulose (HPMC) E5 and Soluplus® were used to formulate nine fuse depositional 3D-printed tablets with different inner core fill densities and outside shell thicknesses. This work reports the successful fabrication of solid-dispersion filaments with an API dispersed in HPMC based matrix via HME technology, and the production of zero order controlled release tablets with different 3D structures (tablets #3, 5, 6, and 9) using a 3D printer.

Rat Palatability Study for Taste Assessment of Caffeine Citrate Formulation Prepared via Hot-Melt Extrusion Technology.

Developing a pediatric oral formulation with an age-appropriate dosage form and taste masking of naturally bitter active pharmaceutical ingredients (APIs) are key challenges for formulation scientists. Several techniques are used for taste masking of bitter APIs to improve formulation palatability; however, not all the techniques are applicable to pediatric dosage forms because of the limitations on the kind and concentration of the excipients that can be used. Hot-melt extrusion (HME) technology is used successfully for taste masking of bitter APIs and overcomes some of the limitations of the existing taste-masking techniques. Likewise, analytical taste assessment is an important quality control parameter evaluated by several in vivo and in vitro methods, such as the human taste panel, electrophysiological methods, electronic sensor, and animal preference tests to aid in selecting a taste-masked formulation. However, the most appropriate in vivo method to assess the taste-masking efficacy of pediatric formulations remains unknown because it is not known to what extent the human taste panel/electronic tongue can predict the palatability in the pediatric patients. The purpose of this study was to develop taste-masked caffeine citrate extrudates via HME and to demonstrate the wide applicability of a single bottle-test rat model to record and compare the volume consumed of the taste-masked solutions to that of the pure API. Thus, this rat model can be considered as a low-cost alternative taste-assessment method to the most commonly used expensive human taste panel/electronic tongue method for pediatric formulations.

Conjugation of Hot-Melt Extrusion with High-Pressure Homogenization: a Novel Method of Continuously Preparing Nanocrystal Solid Dispersions.

Over the past few decades, nanocrystal formulations have evolved as promising drug delivery systems owing to their ability to enhance the bioavailability and maintain the stability of poorly water-soluble drugs. However, conventional methods of preparing nanocrystal formulations, such as spray drying and freeze drying, have some drawbacks including high cost, time and energy inefficiency, traces of residual solvent, and difficulties in continuous operation. Therefore, new techniques for the production of nanocrystal formulations are necessary. The main objective of this study was to introduce a new technique for the production of nanocrystal solid dispersions (NCSDs) by combining high-pressure homogenization (HPH) and hot-melt extrusion (HME). Efavirenz (EFZ), a Biopharmaceutics Classification System class II drug, which is used for the treatment of human immunodeficiency virus (HIV) type I, was selected as the model drug for this study. A nanosuspension (NS) was first prepared by HPH using sodium lauryl sulfate (SLS) and Kollidon® 30 as a stabilizer system. The NS was then mixed with Soluplus® in the extruder barrel, and the water was removed by evaporation. The decreased particle size and crystalline state of EFZ were confirmed by scanning electron microscopy, zeta particle size analysis, and differential scanning calorimetry. The increased dissolution rate was also determined. EFZ NCSD was found to be highly stable after storage for 6 months. In summary, the conjugation of HPH with HME technology was demonstrated to be a promising novel method for the production of NCSDs.

Continuous production of fenofibrate solid lipid nanoparticles by hot-melt extrusion technology: a systematic study based on a quality by design approach.

This contribution describes a continuous process for the production of solid lipid nanoparticles (SLN) as drug-carrier systems via hot-melt extrusion (HME). Presently, HME technology has not been used for the manufacturing of SLN. Generally, SLN are prepared as a batch process, which is time consuming and may result in variability of end-product quality attributes. In this study, using Quality by Design (QbD) principles, we were able to achieve continuous production of SLN by combining two processes: HME technology for melt-emulsification and high-pressure homogenization (HPH) for size reduction. Fenofibrate (FBT), a poorly water-soluble model drug, was incorporated into SLN using HME-HPH methods. The developed novel platform demonstrated better process control and size reduction compared to the conventional process of hot homogenization (batch process). Varying the process parameters enabled the production of SLN below 200 nm. The dissolution profile of the FBT SLN prepared by the novel HME-HPH method was faster than that of the crude FBT and a micronized marketed FBT formulation. At the end of a 5-h in vitro dissolution study, a SLN formulation released 92-93% of drug, whereas drug release was approximately 65 and 45% for the marketed micronized formulation and crude drug, respectively. Also, pharmacokinetic study results demonstrated a statistical increase in Cmax, Tmax, and AUC0-24 h in the rate of drug absorption from SLN formulations as compared to the crude drug and marketed micronized formulation. In summary, the present study demonstrated the potential use of hot-melt extrusion technology for continuous and large-scale production of SLN.

Evaluation of the recrystallization kinetics of hot-melt extruded polymeric solid dispersions using an improved Avrami equation.

The recrystallization of an amorphous drug in a solid dispersion system could lead to a loss in the drug solubility and bioavailability. The primary objective of the current research was to use an improved kinetic model to evaluate the recrystallization kinetics of amorphous structures and to further understand the factors influencing the physical stability of amorphous solid dispersions. Amorphous solid dispersions of fenofibrate with different molecular weights of hydroxypropylcellulose, HPC (Klucel™ LF, EF, ELF) were prepared utilizing hot-melt extrusion technology. Differential scanning calorimetry was utilized to quantitatively analyze the extent of recrystallization in the samples stored at different temperatures and relative humidity (RH) conditions. The experimental data were fitted into the improved kinetics model of a modified Avrami equation to calculate the recrystallization rate constants. Klucel LF, the largest molecular weight among the HPCs used, demonstrated the greatest inhibition of fenofibrate recrystallization. Additionally, the recrystallization rate (k) decreased with increasing polymer content, however exponentially increased with higher temperature. Also k increased linearly rather than exponentially over the range of RH studied.

Crystallization and preliminary X-ray analysis of the RPB5 subunit of human RNA polymerase II.

RPB5 is an essential subunit of eukaryotic RNA polymerase II. It has been proposed to interact with DNA and several key transcription factors during transcription. These interactions are crucial for transcription and its regulation. Here, prior to obtaining complex structures of human RPB5 and its binding partners, recombinant human RPB5 was crystallized alone by vapour diffusion in hanging drops. A complete data set was collected from a single frozen crystal employing an in-house X-ray source. The crystal diffracted to 2.8 Å resolution and belonged to space group P4(3)2(1)2. The likely Matthews coefficient and solvent content of 2.67 Å(3) Da(-1) and 53.92%, respectively, suggested the presence of two protein subunits in the asymmetric unit. The structure was solved using molecular replacement.