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[Display omitted] • The polymorphic selection of three cocrystals via four techniques was investigated. • Solvent selection showed little control via solution evaporation and LAG. • Larger flow rates favour stable polymorphs due to droplet size upon atomization. • DFT computed electron density maps further rationalised polymorphic predominance. Polymorphism can be a valuable tool as well as an impediment in the development and approval of pharmaceuticals, providing an opportunity to tune active pharmaceutical ingredient (API) physicochemical properties. The control of polymorphism in cocrystalline systems and other multicomponent forms remains underexplored. The study herein aims to investigate the potential of several techniques, liquid-assisted grinding (LAG), solvent evaporation (SE), supercritical enhanced atomization (SEA) and electrospraying, to control the cocrystal polymorphic outcome of three cocrystals: isonicotinamide-citric acid (IsoCa), ethenzamide-saccharin (EthSac) and ethenzamide-gentisic acid (EthGa). Solvent selection employing LAG and SE showed little effect on polymorphic outcome. Electrospraying and SEA primarily produced the α form of IsoCa, with process parameter variations leading to the β form during SEA, and a mixture of α and γ from electrospraying. Electrospraying led to the stable form I of EthSac, while SEA could produce pure form II, and a mixture. Electrospraying produced the form I of EthGa while SEA could produce form II, with an unknown polymorphic impurity. Density functional theory (DFT) computed electron density (ED) maps of cocrystal polymorph binary systems further rationalised the polymorphic predominance observed through the electrospraying. Ultimately this study provides a general road map for polymorph selection via atomization-based methodologies. [ABSTRACT FROM AUTHOR]

Children with Phenylketonuria (PKU) and severe cow's milk protein allergy (CMPA) consume prescribed, specially formulated, foods for special medical purposes (FSMPs) as well as restricted amounts of normal foods. These patients are exposed to artificial sweeteners from the consumption of a combination of free and prescribed foods. Young patients with PKU and CMPA have a higher risk of exceeding acceptable daily intakes (ADI) for additives than age-matched healthy children. A predictive modelling approach has been adapted successfully to assess the additive exposure of young patients with PKU and CMPA to artificial sweeteners. Steviol glycosides (E960) are at various stages of regulatory approval for the various food categories in the EU but are not as yet permitted for use in products intended for young children. The aim of this study was to predict potential steviol glycoside exposure in young children with PKU and CMPA considering the potential for future provisions for the use of this sweetener. The recent introduction of steviol glycosides means that no exposure data are available for children with CMPA and PKU. Food consumption data were derived from the food consumption survey data of healthy young children in Ireland from the National Preschool and Nutrition Survey (NPNS, 2010-11). Specially formulated amino acid-based FSMPs are used to replace whole or milk protein foods and were included in the exposure model to replace restricted foods. The recommendations to ensure adequate protein intake in these patients were used to determine FSMP intake. Exposure assessment results indicated that the maximum permitted level (MPL) for FSMPs would warrant careful consideration to avoid exposures above the ADI. These data can be used to inform recommendations for the medical nutrition industry. [ABSTRACT FROM AUTHOR]

The manipulation of both solid-state form and particle size is a versatile means by which physicochemical properties of pharmaceutical drugs may be improved/fine-tuned. The work presented herein describes the solid-state and particle size control of the most recently FDA-approved pharmaceutical cocrystal, composed of two APIs, Celecoxib-Tramadol hydrochloride (Seglentis®), using a continuous atomization technique, namely supercritical CO 2 -assisted nano-spray drying. Using a three-factorial design of experiments, both (co)amorphous and cocrystalline samples were generated, depending on processing conditions. Mean particle sizes ranged from 120 nm to 1160 nm, with solution flow rate showing the most significant effect due to its impact on atomized droplet sizes. While all (co)amorphous samples displayed a similar morphology, one set of conditions produced a (co)amorphous sample with a larger degree of intermolecular interactions, comparable with the hydrogen bonding network observed in the cocrystalline samples. Tabletting of four formulations was carried out to investigate the impact of particle size and solid-state on tabletability, compactability and compressibility. While all formulations performed adequately in these critical quality attributes, the formulations which contained cocrystalline particles underperformed regarding tabletability and compactability due to their irregular shape and larger size. However, due to the increased prevalence of intermolecular interactions, the cocrystalline and (co)amorphous samples with a larger degree of hydrogen bonding led to improved compressibility. [Display omitted] • Production of both (co)amorphous and cocrystalline samples achieved. • (Co)Amorphous samples produced with and without intermolecular interactions. • Mean particle sizes of the produced samples range from 0.12 to 1.16 µm. • Variations recorded within acceptable ranges for tabletability, compressibility, and compactability. [ABSTRACT FROM AUTHOR]

Artificial sweeteners are used in protein substitutes intended for the dietary management of inborn errors of metabolism (phenylketonuria, PKU) to improve the variety of medical foods available to patients and ensure dietary adherence to the prescribed course of dietary management. These patients can be exposed to artificial sweeteners from the combination of free and prescribed foods. Young children have a higher risk of exceeding acceptable daily intakes (ADI) for additives than adults, due to higher food intakes per kg body weight. Young patients with PKU aged 1–3 years can be exposed to higher levels of artificial sweeteners from these dual sources than normal healthy children and are at a higher risk of exceeding the ADI. Standard intake assessment methods are not adequate to assess the additive exposure of young patients with PKU. The aim of this study was to estimate the combination effect on the intake of artificial sweeteners and the impact of the introduction of new provisions for an artificial sweetener (sucralose, E955) on exposure of PKU patients using a validated probabilistic model. Food consumption data were derived from the food consumption survey data of healthy young children in the United Kingdom from the National Diet and Nutrition Survey (NDNS, 1992–2012). Specially formulated protein substitutes as foods for special medical purposes (FSMPs) were included in the exposure model to replace restricted foods. Inclusion of these protein substitutes is based on recommendations to ensure adequate protein intake in these patients. Exposure assessment results indicated the availability of sucralose for use in FSMPs for PKU leads to changes in intakes in young patients. These data further support the viability of probabilistic modelling as a means to estimate food additive exposure in patients consuming medical nutrition products. [ABSTRACT FROM PUBLISHER]

The choice of suitable normal foods is limited for individuals with particular medical conditions, e.g., inborn errors of metabolism (phenylketonuria – PKU) or severe cow’s milk protein allergy (CMPA). Patients may have dietary restrictions and exclusive or partial replacement of specific food groups with specially formulated products to meet particular nutrition requirements. Artificial sweeteners are used to improve the appearance and palatability of such food products to avoid food refusal and ensure dietary adherence. Young children have a higher risk of exceeding acceptable daily intakes for additives than adults due to higher food intakes kg–1body weight. The Budget Method and EFSA’s Food Additives Intake Model (FAIM) are not equipped to assess partial dietary replacement with special formulations as they are built on data from dietary surveys of consumers without special medical requirements impacting the diet. The aim of this study was to explore dietary exposure modelling as a means of estimating the intake of artificial sweeteners by young PKU and CMPA patients aged 1–3 years. An adapted validated probabilistic model (FACET) was used to assess patients’ exposure to artificial sweeteners. Food consumption data were derived from the food consumption survey data of healthy young children in Ireland from the National Preschool and Nutrition Survey (NPNS, 2010–11). Specially formulated foods for special medical purposes were included in the exposure model to replace restricted foods. Inclusion was based on recommendations for adequate protein intake and dietary adherence data. Exposure assessment results indicated that young children with PKU and CMPA have higher relative average intakes of artificial sweeteners than healthy young children. The reliability and robustness of the model in the estimation of patient additive exposures was further investigated and provides the first exposure estimates for these special populations. [ABSTRACT FROM PUBLISHER]

The inability of many biopharmaceutical formulations to retain their structure and integrity when in solution represents a major issue for their transport and storage, reducing their shelf-life and activity/stability. The ability to efficiently produce dried solid dosage forms of biopharmaceuticals such as proteins and nucleic acids allows for many improvements in the way in which these sensitive materials are stored, transported, and administered. While freeze-drying is an established drying method implemented in the biopharmaceutical industry with well-understood challenges, there has been a distinct lack of uptake in the development and usage of spray drying and supercritical fluid drying. These technologies typically provide distinct particles sizes and morphologies, introducing an additional route to improve the final product performance. This review focuses on the key aspects of various supercritical fluid methods reported in the literature to produce dried biopharmaceutical powders with enhanced stability compared to those produced by more conventional methods. [Display omitted] • 168 relevant publications, including more than 50 publications over the past 10 years are reviewed here. • Biomolecules produced by various drying methods are compared on the basis of stability, morphology, and particle size. • Supercritical CO2 offers a unique alternative to conventional methods by means of water removal and high activity retention. [ABSTRACT FROM AUTHOR]

Cholesterol oxidation products or oxysterols are of interest due to their hypothesized role in the development of atherosclerosis. The objective of the present study was to assess the cytotoxic effects of mixtures of oxysterols: 25-hydroxycholesterol (25-OHC), 7 β -hydroxycholesterol (7 β -OHC), and cholesterol-5 β ,6 β -epoxide ( β -epox) on two cell types associated with the atherosclerotic process, bovine aortic endothelial (BAE) cells and human monocytic U937 cells. Cells were exposed to 25-OHC, 7 β -OHC, or β -epox, or equimolar mixtures (30 μ M) of 25-OHC and 7 β -OHC, 25-OHC and β -epox, or 7 β -OHC and β -epox for 48 h. Cell viability was assessed using the fluorescein diacetate/ethidium bromide (FDA/ EtBr) assay and nuclear morphology following staining with Hoechst 33342. 25-OHC was the least toxic of the oxysterols and did not induce apoptosis in either cell line. Both 7 β -OHC and β -epox treatments were cytotoxic and induced apoptosis in the cells. Cotreatment with 25-OHC did not alter the toxicity of 7 β -OHC and β -epox in U937 cells but did decrease the percentage apoptotic cell death. In contrast, in the BAE cells cotreatment with 25-OHC had a slight protective effect on 7 β -OHC and β -epox–induced toxicities and a marked decrease in apoptotic cell death. The 7 β -OHC and β -epox mixture induced a significant increase in apoptotic cell death in U937 cells but decreased this mode of cell death in the BAE cells. The effects of oxysterols on glutathione levels also differed between the cells with changes noted in U937 and not in BAE cells. Results demonstrate interactive effects when oxysterols are studied as mixtures rather than single compounds in vitro. [ABSTRACT FROM AUTHOR]

Children with phenylketonuria (PKU) and severe cow's milk protein allergy (CMPA) consume prescribed, specially formulated, foods for special medical purposes (FSMPs) in addition to having restricted intake of normal foods. These vulnerable patients are exposed to artificial sweeteners from the consumption of a combination of both free and prescribed foods. Young patients with PKU and CMPA aged from 1 to 3 years have a higher risk of exceeding the acceptable daily intake (ADI) for sweeteners than age-matched healthy children. A probabilistic modelling approach has been adapted successfully to assess the exposure of young patients with PKU and CMPA to low-calorie sweeteners. To assist professionals in the screening and formulation of foods containing food additives for such patients, a simplified exposure method/tool has been developed. The tool is intended to ensure that total dietary exposure can be considered. The simplified tool is not intended to replace the probabilistic model but may be used as a screening tool to determine if further investigation on exposure is warranted. The aim of this study was to develop and validate this simplified exposure tool to support those currently used by healthcare professionals (HCPs) using data available from the probabilistic modelling of exposure in young children with PKU and CMPA. The probabilistic model does not allow for swift screening of exposure scenarios nor is the present EFSA Food Additive Intake Assessment Model (FAIM) fully suitable for application to medical foods. The simplified exposure tool in medical nutrition (SETIM) reported here is both reliable and consistent and provides additive usage levels which minimise regular exposure above the ADI in patients. In addition to the usefulness of SETIM for the medical nutrition industry, the tool has the potential to enhance the practice of evidence-based medical nutrition by official risk assessment bodies, registration authorities and healthcare professionals.