Cracking the code for continuous processing and personalised medicine

Personalised medicine is the next great global challenge for the pharmaceutical industry. The vision of the pharmacy of the future is one in which pharmacies employ disruptive technologies to enable on-demand manufacture of drugs designed to individual needs. For example, multiple medications may be prescribed that treat a patient’s exact age-profile and medical history. These medications could then be 3D printed into one tablet, on-demand at the patient’s local drug supplier Central to this vision is the concept of continuous processing. Currently, active pharmaceutical ingredients (APIs) are manufactured in large batches at distinctly separate times. Continuous processing replaces this large-batch process with the manufacture of lower volumes but at a constant rate. This process enables the continuous flow of product, reduces inventories, and has less batch-to-batch variation, giving higher process control and higher quality. Researchers led by Prof Gavin Walker at the Bernal Institute, University of Limerick (UL), are generating the chemical engineering solutions for the challenges of personalised medicine. This highly cited research is changing how we train chemical engineers, impacting industry competitiveness, and attracting R&D investment into Ireland

Recent strategies in spray drying for the enhanced bioavailability of poorly water-soluble drugs

Poorly water-soluble drugs are a significant and ongoing issue for the pharmaceutical industry. An overview of recent developments for the preparation of spray-dried delivery systems is presented. Examples include amorphous solid dispersions, spray dried dispersions, microparticles, nanoparticles, surfactant systems and self-emulsifying drug delivery systems. Several aspects of formulation are considered, such as pre-screening, choosing excipient(s), the effect of polymer structure on performance, formulation optimisation, ternary dispersions, fixed-dose combinations, solvent selection and component miscibility. Process optimisation techniques including nozzle selection are discussed. Comparisons are drawn with other preparation techniques such as hot melt extrusion, freeze drying, milling, electro spinning and film casting. Novel analytical and dissolution techniques for the characterization of amorphous solid dispersions are included. Progress in understanding of amorphous supersaturation or recrystallisation from solution gathered from mechanistic studies is discussed. Aspects of powder flow and compression are considered in a section on downstream processing. Overall, spray drying has a bright future due to its versatility, efficiency and the driving force of poorly soluble drug

Effective separation of prime olefins from gas stream using anion pillared metal organic frameworks: ideal adsorbed solution theory studies, cyclic application and stability

The separation of C3H4/C3H6 is one of the most energy intensive and challenging operations, requiring up to 100 theoretical stages, in traditional cryogenic distillation. In this investigation, the potential application of two MOFs (SIFSIX-3-Ni and NbOFFIVE-1-Ni) was tested by studying the adsorption-desorption behaviors at a range of operational temperatures (300–360 K) and pressures (1–100 kPa). Dynamic adsorption breakthrough tests were conducted and the stability and regeneration ability of the MOFs were established after eight consecutive cycles. In order to establish the engineering key parameters, the experimental data were fitted to four isotherm models (Langmuir, Freundlich, Sips and Toth) in addition to the estimation of the thermodynamic properties such as the isosteric heats of adsorption. The selectivity of the separation was tested by applying ideal adsorbed solution theory (IAST). The results revealed that SIFSIX-3-Ni is an effective adsorbent for the separation of 10/90 v/v C3H4/C3H6 under the range of experimental conditions used in this study. The maximum adsorption reported for the same combination was 3.2 mmol g−1. Breakthrough curves confirmed the suitability of this material for the separation with a 10-min gab before the lighter C3H4 is eluted from the column. The separated C3H6 was obtained with a 99.98% purity

High purity/recovery separation of propylene from propyne using anion pillared metal-organic framework: application of vacuum swing adsorption (VSA)

Propylene is one of the world’s most important basic olefin raw material used in the production of a vast array of polymers and other chemicals. The need for high purity grade of propylene is essential and traditionally achieved by the very energy-intensive cryogenic separation. In this study, a pillared inorganic anion SIF6 2− was used as a highly selective C3H4 due to the square grid pyrazine based structure. Single gas adsorption revealed a very high C3H4 uptake value (3.32, 3.12, 2.97 and 2.43 mmol·g −1 at 300, 320, 340 and 360 K, respectively). The values for propylene for the same temperatures were 2.73, 2.64, 2.31 and 1.84 mmol·g −1 respectively. Experimental results were obtained for the two gases fitted using Langmuir and Toth models. The former had a varied degree of representation of the system with a better presentation of the adsorption of the propylene compared to the propyne system. The Toth model regression offered a better fit of the experimental data over the entire range of pressures. The representation and fitting of the models are important to estimate the energy in the form of the isosteric heats of adsorption (Qst), which were found to be 45 and 30 kJ·Kmol−1 for propyne and propylene, respectively. A Higher Qst value reveals strong interactions between the solid and the gas. The dynamic breakthrough for binary mixtures of C3H4/C3H6 (30:70 v/v)) were established. Heavier propylene molecules were eluted first from the column compared to the lighter propyne. Vacuum swing adsorption was best suited for the application of strongly bound materials in adsorbents. A six-step cycle was used for the recovery of high purity C3H4 and C3H6. The VSA system was tested with respect to changing blowdown time and purge time as well as energy requirements. It was found that the increase in purge time had an appositive effect on C3H6 recovery but reduced productivity and recovery. Accordingly, under the experimental conditions used in this study for VSA, the purge time of 600 s was considered a suitable trade-off time for purging. Recovery up to 99%, purity of 98.5% were achieved at a purge time of 600 s. Maximum achieved purity and recovery were 97.4% and 98.5% at 100 s blowdown time. Energy and power consumption varied between 63–70 kWh/ton at the range of purge and blowdown time used. The VSA offers a trade-off and cost-effective technology for the recovery and separation of olefins and paraffin at low pressure and high purit

Solid sorbents as a retrofit technology for CO2 removal from natural gas under high pressure and temperature conditions

The capture of CO2 under high pressure and temperature is challenging and is required in a number for industrial applications including natural gas processing. In this work, we examine the use of benchmark hybrid ultraporous materials HUMs for their potential use in CO2 adsorption processes under high-pressure conditions, with three varying temperatures (283, 298 and 318 K). NbOFFOVE-1-Ni and SIFSIX-3-Ni were the selected HUMs given their established superior CO2 capacity under low pressure (0â 1 bar). Both are microporous with highly ordered crystalline structures as compared to the mesoporous hexagonal silica (Santa Barbara Anhydrous-15 (SBA-15)). SBA-15 was previously tested for both low and high-pressure applications and can serve as a benchmark in this study. Sorbent characterization using XRD, SEM, FTIR and N2 adsorption were conducted to assure the purity and structure of the sorbents. TGA analysis were conducted to establish the thermal stability of the sorbents under various temperatures. High-pressure CO2 adsorption was conducted from 0â 35 bar using magnetic suspension balance (Rubotherm). Although the SBA-15 had the highest surface (527 m3/g) are of the three adsorbents, the CO2 adsorption capacity (0.42 mmol/g) was an order of magnitude less than the studies HUMs with SIFSIX-3-Ni having 2.6 mmol/g, NbOFFIVE-1-Ni achieving 2.5 mmol/g at 298 K. Multistage adsorption isotherms were obtained at different pressures. In addition, results indicate that electrostatics in HUMs are most effective at improving isosteric heat of adsorption Qst and CO2 uptake. Higher temperatures had negative effect on adsorption capacity for the HUMs and SBA-15 at pressures between 7- 9 bar. In SAB-15 the effect of temperature is reversed in what is known as a cross over phenomena

Incomplete cocrystalization of ibuprofen and nicotinamide and its interplay with formation of ibuprofen dimer and/or nicotinamide dimer: a thermodynamic analysis based on DFT data

Cocrystallization of ibuprofen and nicotinamide in hot melt extrusion process has been subject of many studies addressing low ibuprofen bioavailability. However, it is observed that the process of cocrystal formation of ibuprofen and nicotinamide might be incomplete. We hypothesized that formation of dimers of ibuprofen–ibuprofen or dimers nicotinamide– nicotinamide might be the cause of such poor cocrystalization process by altering the phase behaviour of the mixture. This paper addresses the molecular thermodynamics of mixtures of ibuprofen and nicotinamide, with special focus on the possibility of formation of these dimers and their corresponding interplay with mixture phase behaviour. For this purpose, density functional theory calculations are used to calculate electron donor-acceptor sizes on each molecule and accordingly possible dimers of each molecule are analysed. The free energies and phase diagram are determined for (1) when a dimer is formed or (2) no dimer is formed, over a wide operating temperature range of 273.15 K–390 K. The binding and solvation energies are calculated to identify/rank dimers. Calculations showed that formation of dimers requires an energy input which can be accessible noting to the external heating in hot melt extrusion process. The calculated solvation energies of the dimers suggest that addition of liquid binder (water) can mitigate the risk of dimer formations. Addition of proper binder/excipient is an easy route to compensate such dimer formation and to engineer ibuprofen and nicotinamide cocrystallization behaviour

Downstream processing of a ternary amorphous solid dispersion: the impacts of spray drying and hot melt extrusion on powder flow, compression and dissolution

Downstream processing aspects of a stable form of amorphous itraconazole exhibiting enhanced dissolution properties were studied. Preparation of this ternary amorphous solid dispersion by either spray drying or hot melt extrusion led to significantly different powder processing properties. Particle size and morphology was analysed using scanning electron microscopy. Flow, compression, blending and dissolution were studied using rheometry, compaction simulation and a dissolution kit. The spray dried material exhibited poorer flow and reduced sensitivity to aeration relative to the milled extrudate. Good agreement was observed between differing forms of flow measurement, such as Flow Function, Relative flow function, Flow rate index, Aeration rate, the Hausner ratio and the Carr index. The stability index indicated that both powders were stable with respect to agglomeration, de-agglomeration and attrition. Tabletability and compressibility studies showed that spray dried material could be compressed into stronger compacts than extruded material. Blending of the powders with low moisture, freely-flowing excipients was shown to influence both flow and compression. Porosity studies revealed that blending could influence the mechanism of densification in extrudate and blended extrudate formulations. Following blending, the powders were compressed into four 500 mg tablets, each containing a 100 mg dose of amorphous itraconazole. Dissolution studies revealed that the spray dried material released drug faster and more completely and that blending excipients could further influence the dissolution rate

Controlling polymorphism of carbamazepine nanoparticles in a continuous supercritical-CO2-assisted spray drying process

Controlling polymorphism in the transition from batch to continuous crystallization represents a major obstacle for the pharmaceutical industry. This work demonstrates a novel methodology to control the polymorphism of carbamazepine (CBZ) nanoparticles, a highly polymorphic BCS class II drug, using a continuous supercritical CO2 antisolvent-assisted nano spray drying (SASD) process. We show herein that when supersaturation conditions are achieved in the high-pressure SASD nozzle in the presence of anionic additives (e.g. sodium stearate, sodium dodecyl sulfate), nanoparticles of the metastable CBZ form II (using sodium stearate) or the stable CBZ form III (using sodium dodecyl sulfate) are obtained from methanol solutions, respectively. This novel methodology provides control over the final polymorphic form of CBZ obtained by (1) templating the desired polymorphic form when supercritical CO2 supersaturates the CBZ-additive methanol solution in the nozzle and (2) avoiding/minimizing the occurrence of any possible polymorphic transformation by immediately spray drying the supercritical antisolvent induced suspension into a dried fine powder. These results contrast with those obtained when using non-supersaturating conditions in the SASD nozzle (amorphous CBZ is obtained, regardless of the additive used) and when using conventional spray drying (SD) where there is no antisolvent effect in the nozzle (CBZ form IV is obtained, regardless of the additive used). The impact that the mass ratio of methanol and supercritical CO2 has on the supersaturation and consequently on the polymorphic outcome of carbamazepine obtained from batch and continuous supercritical CO2 antisolvent crystallization processes is also discussed

Optimisation of a two-liquid component pre-filled acrylic bone cement system: a design of experiments approach to optimise cement final properties

The initial composition of acrylic bone cement along with the mixing and delivery technique used can influence its final properties and therefore its clinical success in vivo. The polymerisation of acrylic bone cement is complex with a number of processes happening simultaneously. Acrylic bone cement mixing and delivery systems have undergone several design changes in their advancement, although the cement constituents themselves have remained unchanged since they were first used. This study was conducted to determine the factors that had the greatest effect on the final properties of acrylic bone cement using a pre-filled bone cement mixing and delivery system. A design of experiments (DoE) approach was used to determine the impact of the factors associated with this mixing and delivery method on the final properties of the cement produced. The DoE illustrated that all factors present within this study had a significant impact on the final properties of the cement. An optimum cement composition was hypothesised and tested. This optimum recipe produced cement with final mechanical and thermal properties within the clinical guidelines and stated by ISO 5833 (International Standard Organisation (ISO), International standard 5833: implants for surgery-acrylic resin cements, 2002), however the low setting times observed would not be clinically viable and could result in complications during the surgical technique. As a result further development would be required to improve the setting time of the cement in order for it to be deemed suitable for use in total joint replacement surgery

Creating cocrystals: a review of pharmaceutical cocrystal preparation routes and applications

Originally discovered almost a century ago, cocrystals continue to gain interest in the modern day due to their ability to modify the physical properties of solid-state materials, particularly pharmaceuticals. Intensification of cocrystal research efforts has been accompanied by an expansion of the potential applications where cocrystals can offer a benefit. Where once solubility manipulation was seen as the primary driver for cocrystal formation, cocrystals have recently been shown to provide attractive options for taste masking, mechanical property improvement, and intellectual property generation and extension. Cocrystals are becoming a commercial reality with a number of cocrystal products currently on the market and more following in registration and clinical trial phases. Increased commercialization of cocrystals has in turn necessitated additional research on methods to make cocrystals, with particular emphasis placed on emerging technologies that can offer environmentally attractive and efficient options. Methods of producing cocrystals and of harnessing the bespoke physical property adjustment provided by cocrystals are reviewed in this article, with a particular focus on emerging trends in these areas