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Drug-mediated correction of abnormal biological zinc homeostasis could provide new routes to treating neurodegeneration, cancer, and viral infections. Designing therapeutics to facilitate zinc transport intracellularly is hampered by inadequate concentrations of endogenous zinc, which is often protein-bound in vivo. We found strong evidence that hydroxychloroquine, a drug used to treat malaria and employed as a potential treatment for COVID-19, does not bind and transport zinc across biological membranes through ionophoric mechanisms, contrary to recent claims. In vitro complexation studies and liposomal transport assays are correlated with cellular zinc assays in A549 lung epithelial cells to confirm the indirect mechanism of hydroxychloroquine-mediated elevation in intracellular zinc without ionophorism. Molecular simulations show hydroxychloroquine-triggered helix perturbation in zinc-finger protein without zinc chelation, a potential alternative non-ionophoric mechanism.

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Nowadays, sustainable materials are receiving significant attention due to the fact that they will be crucial for the development of the next generation of products and devices. In the present work, hydrogels have been successfully synthesized using lignin which is non-valorized biopolymer from the paper industry. Hydrogels were prepared via crosslinking with Poly(ethylene) glycol diglycidyl ether (PEGDGE). Different crosslinker ratios were used to determine their influence on the structural and chemical properties of the resulting hydrogels. It has been found that pore size was reduced by increasing crosslinker amount. The greater crosslinking density increased the swelling capacity of the hydrogels due to the presence of more hydrophilic groups in the hydrogel network. Paracetamol release test showed higher drug diffusion for hydrogels produced with a ratio lignin:PEGDGE 1:1. The obtained results demonstrate that the proposed approach is a promising route to utilize lignocellulose waste for producing porous materials for advanced biomedical applications in the pharmacy industry.

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Discovery of novel cocrystal systems and improvement of their physicochemical properties dominates the current literature on cocrystals yet the required end-product formulation is rarely addressed. Drug product manufacturing includes complex API solid state processing steps such as milling, granulation, and tableting. These all require high mechanical stress which can lead to solid-state phase transformations into polymorphs and solvates, or lead to dissociation of cocrystals into their individual components. Here we measured the effect of tablet excipients on solid-state processing of a range of pharmaceutical cocrystal formulations. Our findings were rationalised using Density Functional Theory (DFT) calculations of intermolecular binding energies of cocrystal constituents and co-milling excipients. A 1:1 stoichiometric ratio of API Theophylline (THP) and co-former 4-Aminobenzoic acid (4ABA) was co-milled with five different excipients: hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), lactose, and microcrystalline cellulose (MCC). The experiments were carried out in 10 and 25 ml milling jars at 30 Hz for different milling times. Co-milled samples were characterised for formation of cocrystals and phase transformation using powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). Our data shows that co-milling in the presence of PEG, HMPC or lactose yields purer cocrystals, supported by the calculated stronger excipient interactions for PVP and MCC. We identify a suitably-prepared THP-4ABA pharmaceutical cocrystal formulation that is stable under extended milling conditions.

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In this study, an image processing technique is implemented to measure complete two-dimensional particle size and liquid content distribution (2D-distribution) of the granules produced in twin screw granulation (TSG). The effects of liquid binder viscosity and liquid to solid ratio (L/S) on the 2D-distribution, and the residence time distribution were studied. The effect of screw configuration on granule formation at different conditions was also investigated, were the mean residence time distribution (MRTD) in conveying elements decreases with the increase of L/S ratio and viscosity. While in kneading elements the MRTD decreases with the increase of L/S and increases with the increase of viscosity. The mean liquid saturation level of the granule is exponentially related to its size. As well, the increase in binder viscosity and L/S ratio leads to more uneven/bi-model particle size distribution (PSD) in the conveying elements, while kneading elements change the initial bi-model PSDs into more homogenous mono-model like distributions.

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The mechanical properties of powders determine the ease of manufacture and ultimately the quality of the oral solid dosage forms. Although poor mechanical properties of an active pharmaceutical ingredient (API) can be mitigated by using suitable excipients in a formulation, the effectiveness of that approach is limited for high dose drugs or multidrug tablets. In this context, improving the mechanical properties of the APIs through solid form optimisation is a good strategy to address such a challenge. This work explores the powder and tableting properties of various lamotrigine (LAM) solid forms with the aim to facilitate direct compression by overcoming the poor tabletability of LAM. The two drug-drug crystals of LAM with nicotinamide and valproic acid demonstrate superior flowability and tabletability over LAM. The improved powder properties are rationalised by structure analysis using energy framework, scanning electron microscopy, and Heckel analysis.

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In the pharmaceutical manufacturing, drug release behavior development is remained as one of the main challenges to improve the drug effectiveness. Recently, more focus has been done on using mesoporous silica materials as drug carriers for prolonged and superior control of drug release in human body. In this study, release behavior of paracetamol is developed using drug-loaded KCC-1-NH2 mesoporous silica, based on direct compaction method for preparation of tablets. The purpose of this study is to investigate the utilizing of pure KCC-1 mesoporous silica (KCC-1) and amino functionalized KCC-1 (KCC-1-NH2) as drug carriers in oral solid dosage formulations compared to common excipient, microcrystalline cellulose (MCC), to improve the control of drug release rate by manipulating surface chemistry of the carrier. Different formulations of KCC-1 and KCC-NH2 are designed to investigate the effect of functionalized mesoporous silica as carrier on drug controlled-release rate. The results displayed the remarkable effect of KCC-1-NH2 on drug controlled-release in comparison with the formulation containing pure KCC-1 and formulation including MCC as reference materials. The pure KCC-1 and KCC-1-NH2 are characterized using different evaluation methods such as FTIR, SEM, TEM and N2 adsorption analysis.

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In this study, a complete two dimensional (internal coordinates) population balance model (2D-PBM) is developed, calibrated and validated as a predictive tool for predicting the particle size and the liquid content distribution of the granules produced from twin screw granulation (TSG). The model is calibrated and validated using experimental distributions for the two internal coordinates that are captured using image processing. Granulation runs are conducted at multiple liquid to solid (L/S) ratios and liquid binder viscosities, and then used to calibrate and validate the 2D-PBM. The mathematical model accounts for aggregation and breakage of the particles occurring in three zones of the TSG with inhomogeneous screw configurations (2 conveying zones and 1 kneading zone). A Madec aggregation kernel, and a linear breakage selection function are used in the 2D-PBM and finite volume numerical approximation is used for solving the model. The calibrated model shows that the aggregation rate in the conveying elements is higher than in the kneading elements while the breakage rate in the kneading elements is much higher than in the conveying elements. Also, the increase in L/S ratio and liquid viscosity leads to higher aggregation rates and lower breakage rates.

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Physisorbent metal-organic materials (MOMs) have shown benchmark performance for highly selective CO2 capture from bulk and trace gas mixtures. However, gas stream moisture can be detrimental to both adsorbent performance and hydrolytic stability. One of the most effective methods to solve this issue is to transform the adsorbent surface from hydrophilic to hydrophobic. Herein, we present a facile approach for coating MOMs with organic polymers to afford improved hydrophobicity and hydrolytic stability under humid conditions. The impact of gas stream moisture on CO2 capture for the composite materials was found to be negligible under both bulk and trace CO2 capture conditions with significant improvements in regeneration times and energy requirements.

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: The effect of cooling on the degree of crystallinity, solid-state and dissolution properties of multi-component hot-melt extruded solid dispersions [SD] is of great interest for the successful formulation of amorphous SDs and is an area that is unreported, especially in the context of improving the stability of these specific systems. The thermal solid-state properties, degree of crystallinity, drug-polymer interactions, solubility and physical stability over time were investigated. X-ray powder diffraction [XRPD] and hyper differential scanning calorimetry [DSC] confirmed that indomethacin [INM] was converted to the amorphous state; however, the addition of poloxamer 407 [P407] had a significant effect on the degree of crystallinity and the solubility of the SD formulations. Spectroscopy studies identified the mechanism of interaction and solubility studies, showing a higher dissolution rate compared to amorphous and pure INM in pH 1.2 with a kinetic solubility of 20.63 µg/mL and 34.7 µg/mL after 3 and 24 h. XRPD confirmed that INM remained amorphous after 5 months stability testing in solid solutions with Poly(vinylpyrrolidone-co-vinyl acetate) [PVP VA64] and Plasdone S-630 [PL-S630]. Although cooling had a significant effect on the degree of crystallinity and on solubility of INM, the cooling method used did not have any significant effect on the amorphous stability of INM over time.

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In this study, a compartmental population balance model (CPBM) is developed as a predictive tool of particle size distribution (PSD) for wet granulation in co-rotating twin-screw granulator (TSG). This model is derived in terms of liquid to solid ratio (L/S) and screw speed representing the main process parameters of the TSG. The mathematical model accounts for aggregation and breakage of the particles occurring in five compartments of the TSG with inhomogeneous screw configurations (3 conveying zones and 2 kneading zones). Kapur's aggregation kernel is implemented in granulation and finite volume numerical method is adapted for solving the mathematical model. The results show a dramatic improvement in solution accuracy compared to the cell average numerical method. Moreover, Kriging interpolation is used to interpolate for new values of empirical parameters at different L/S and screw speeds. Finally, the CPBM model is calibrated and validated using the experimental data.

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The use of chitosan as a potential excipient in pharmaceutical formulations for the delivery of drugs produced via direct compression tableting has been investigated. Chitosan, N-cinnamyl substituted O-amine functionalized chitosan (cinnamyl-chitosan) and microcrystalline cellulose (MCC) were formulated, alongside acetaminophen as the active pharmaceutical ingredient (API), and magnesium stearate (Mg-St) as lubricant in a series of formulated blends. A control blend of MCC, acetaminophen (20 wt%) and Mg-St (0.5 wt%) was studied alongside two chitosan-bearing blends, containing 20 wt% chitosan and 20 wt% cinnamyl-chitosan separately. Particle size, shape and morphology of the raw powders were studied along with flowability of both raw powders and formulated powder blends. A single-punch tablet machine was used for tablet compaction. The relationship between tablet hardness and compression pressure was evaluated, while the plasticity factor (PF) and elasticity factor (EF) were derived from force-displacement curves. Disintegration and dissolution studies were also carried out to investigate the drug delivery potential of the blends. Blends containing chitosan and cinnamyl-chitosan possess good compaction properties with high elasticity due to their large particle sizes, and show excellent dissolution properties, releasing >80% API within 30 min. With good mechanical strength and superior drug delivery performance, in addition to its enhanced antibacterial and antioxidative effect gained though chemical modification, cinnamyl-chitosan exhibits potential to be used as a new cost-effective pharmaceutical excipient in direct compression tableting.

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Achieving a uniform extraction of soluble material from a porous matrix is a generic problem in various separation and filtration operations, with applications in the food processing, chemical and pharmaceutical industries. This paper describes models of fluid flow and transport of soluble material within a packed granular bed in the context of coffee extraction. Coffee extraction is described by diffusion of soluble material from particles of one or more representative sizes into fluid flowing through the packed bed. One-dimensional flow models are compared to computational fluid dynamics (CFD) models. A fine and a coarse coffee grind are considered. Model results are compared to experimental data for a packed cylindrical coffee bed and the influence of a change in geometry to a truncated cone is considered. Non-uniform flow in the truncated cone causes significant variation in the local extraction level. Coffee extraction levels during brewing are analysed using extraction maps and the degree of variation is represented on the industry standard coffee brewing control chart. A high variation in extraction yield can be expected to impart bitter flavours into the brew and thus is an important variable to quantify.

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In this work a cocrystal of Theophylline and 4Aminobenzoic acid was successfully produced and formulated using a hydrophilic binder with a novel continuous melt granulation approach. This melt granulation was followed with direct compression to generate oral solid dosage forms. The study revealed that the processing temperature, molecular weight of the binder and binder concentration were the most effective parameters for the production and formulation of high purity cocrystals. Superior tableting performance was observed for melt granulated cocrystals as compared with extruded cocrystals and pure theophylline. Moreover the prepared THP-4ABA melt granulated cocrystals were stable for 14 days (50 °C and 75% RH).

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In this work, the transfer of oral solid dosage forms, currently manufactured via wet granulation, to a continuous direct compression process was considered. Two main challenges were addressed: (1) a poorly flowing API (Canagliflozin) and (2) high drug loading (51 wt%). A scientific approach was utilised for formulation development, targeting flow and compaction behaviour suitable for manufacturing scale. This was achieved through systematic screening of excipients to identify feasible formulations. Targeted design of experiments based on factors such as formulation mixture and processing parameters were utilised to investigate key responses for tablet properties, flow and compaction behaviour. Flow behaviour was primarily evaluated from percentage compressibility and shear cell testing on a powder flow rheometer (FT4). The compaction behaviour was studied using a compaction simulator (Gamlen). The relationships between tablet porosity, tensile strength and compaction pressure were used to evaluate tabletability, compactibility and compressibility to assess scale-up. The success of this design procedure is illustrated by scaling up from the compaction simulator to a Riva Piccola rotary tablet press, while maintaining critical quality attributes (CQAs). Compactibility was identified as a suitable scale-up relationship. The developed procedure should allow accelerated development of formulations for continuous direct compression.

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The influence of lignin modification on drug release and pH-dependent releasing behavior of oral solid dosage forms was investigated using three different formulations. The first formulation contains microcrystalline cellulose (MCC 101) as the excipient and paracetamol as the active pharmaceutical ingredient (API). The second formulation includes Alcell lignin and MCC 101 as the excipient and paracetamol, and the third formulation consists of carboxylated Alcell lignin, MCC 101 and paracetamol. Direct compaction was carried out in order to prepare the tablets. Lignin can be readily chemically modified due to the existence of different functional groups in its structure. The focus of this investigation is on lignin carboxylation and its influence on paracetamol control release behavior at varying pH. Results suggest that carboxylated lignin tablets had the highest drug release, which is linked to their faster disintegration and lower tablet hardness.

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Two-dimensional population balance model (PBM) is developed in order to model pharmaceutical granules formation in a twin-screw wet granulator. Granule size and liquid content are considered as internal coordinates, while axial length of granulator is considered as external coordinate. Two types of initial liquid distribution are considered for the model development, i.e. constant and linear distributions. The main focus is on modeling and validation of liquid content distribution of granules. Regime-separated approach was used in order to capture the non-homogeneity of the granulator. The plug flow regime is considered for the conveying zone, while well-mixed regime is assumed for the kneading zone of twin-screw granulator. Aggregation and breakage are considered as the main mechanisms for granule formation and size control. Cell average method is used for solution of the PBM based on lumped parameter approach. In order to determine experimentally the distribution of liquid, liquid binder by dye addition was used in the process. The model findings are calibrated and validated by comparing with measured liquid content in each size fraction. The measured data is collected on a 12 mm twin-screw wet granulator using microcrystalline cellulose (MCC) and water soluble dye plus water as binder. The model indicated to be valid for MCC and needs to be validated with further excipients. The results revealed that increasing screw speed led to more uniform liquid distribution. Finally, the model findings indicated that 2D PBM is capable of predicting liquid distribution, and can be used as predictive tool in pharmaceutical continuous granulation.

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Modeling of hydrothermal carbonization (HTC) of poultry litter to high-value materials was conducted in order to understand the process and predict the influence of process parameters on product properties. Reaction temperature and time were considered as inputs, whereas carbon and inorganic phosphorous recovery were considered as responses in the model. Artificial neural network (ANN) model was used in order to correlate the process parameters to the outputs. The model was trained and validated using the data collected from HTC experiments carried out at temperatures between 150 ≤ T ≤ 300 °C, and residence time between 30 ≤ t ≤ 480 min. In order to improve the predictability of ANN, more theoretical data points were generated using Kriging approach based on the available measured data. Kriging interpolation improved the ANN model dramatically in training and validation phases, where the carbon recovery model fitting was improved by 0.94% and 9.2% in training and validation respectively, and the inorganic phosphorous (IP) recovery model fitting was improved by a staggering 16.4% and 19.6% in training and validation respectively. This improvement is also reflecting on the derived profiles of carbon and IP recovery in terms of the process parameters. The validated model was then used to understand the effect of process parameters on the response. It was revealed that temperature has more significant effect on the carbon and phosphorous recovery, while the effect of reaction time is more important at low reaction temperatures. The derived profiles shows a monotonic increase in IP recovery and a monotonic decrease in Carbon recovery at higher temperatures and time, this is due to multiple mechanism occurring simultaneously in the HTC reactor at various temperatures and times.

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The field of pharmaceutical cocrystals has reached a tipping point, particularly because cocrystals can improve the physicochemical properties of drugs without compromising their therapeutic benefit. Accounts of cocrystal investigations in the literature started in earnest in 2003 and patent applications soon followed. The frequency of both has steadily accelerated, demonstrating an enhanced understanding of the design, characterisation, and manufacture of cocrystals and heightened interest from industry. Indeed, there were four new product approvals from 2014 to 2017 and more are in the pipeline. Here, we review all marketed drug products that are based upon pharmaceutical cocrystal drug substances, starting with the first recorded example, Beta-Chlor® in 1963, with a particular emphasis on their discovery, rationale for use, and market impact.

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The main focus of this paper is on the improvement of formulations utilising non-conventional bio-based excipients to improve tablet release rates. Two different formulations were considered. The first formulation contains Alcell lignin, lactose monohydrate and microcrystalline cellulose as excipients and acetylsalicylic acid (aspirin) as active pharmaceutical ingredient (API). The second formulation contains lactose monohydrate and microcrystalline cellulose as excipients and aspirin as API. The prepared formulations were roller compacted followed by milling, sieving, and tableting. The tablets were then characterised in terms of dissolution rate in order to compare the release rates. Results indicated that tablets containing Alcell lignin have quicker release, faster disintegration times and higher tablet hardness for all samples with differing process parameters. Higher API dissolution has been attributed to the amorphous structure of lignin and its interaction with aspirin, which increases dissolution of the API.

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Active pharmaceutical ingredients (APIs) are most commonly formulated and delivered to patients in the solid state. Recently, an alternative API solid-state form, namely the pharmaceutical cocrystal, has witnessed increasing academic and industrial interest due to its potential to deliver bespoke physical properties in the pharmaceutical drug product. This interest has been supported by advances in cocrystal discovery, development, and approval, enabled primarily by a supportive new FDA guidance in February 2018. In this review, we describe the process of developing a pharmaceutical cocrystal drug product from screening to approval, with an emphasis on significant developments over the past decade.

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