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This study reports the application of hierarchical porous monoliths as carriers for controlled and dose-adjustable release of model pharmaceutical (dexketoprofen, DEX). The synthesis and detailed characterization of the hierarchical porous scaffolds are provided before and after the adsorption of three doses of DEX─a widely used nonsteroidal anti-inflammatory drug. The drug incorporated in the mesopores of silica was stabilized in an amorphous state, while the presence of macropores provided sufficient space for drug crystallization as we demonstrated via a combination of powder X-ray diffraction, differential scanning calorimetry, and imaging techniques (scanning electron microscopy and EDX analysis). Drug release from silica matrices was tested, and a mechanistic model of this release based on the Fick diffusion equation was proposed. The hierarchical structure of the carrier, due to the presence of micrometric macropores and nanometric mesopores, turned out to be critical for the control of the drug phase and drug release from the monoliths. It was found that at low drug content, the presence of an amorphous component in the pores promoted the rapid release of the drug, while at higher drug contents, the presence of macropores favored the crystallization of DEX, which naturally slowed down its release. Both the hierarchical porous structure and the control of the drug phase (amorphous and/or crystalline) were proven important for adjustable (fast or prolonged) release kinetics, desirable for effective pharmacotherapy and patient compliance. Therefore, the developed materials may serve as a versatile formulation platform for the smart manipulation of drug release kinetics.

Nanoemulsions are considered as the most promising solution to improve the delivery of ophthalmic drugs. The design of ophthalmic nanoemulsions requires an extensive understanding of pharmaceutical as well as technological aspects related to the selection of excipients and formulation processes. This Review aims at providing the readers with a comprehensive summary of possible compositions of nanoemulsions, methods for their formulation (both laboratory and industrial), and differences between technological approaches, along with an extensive outline of the research methods enabling the confirmation of in vitro properties, pharmaceutical performance, and biological activity of the obtained product. The composition of the formulation has a major influence on the properties of the final product obtained with low-energy emulsification methods. Increasing interest in high-energy emulsification methods is a consequence of their scalability important from the industrial perspective. Considering the high-energy emulsification methods, both the composition and conditions of the process (e.g., device power level, pressure, temperature, homogenization time, or number of cycles) are important for the properties and stability of nanoemulsions. It is advisible to determine the effect of each parameter on the quality of the product to establish the optimal process parameters’ range which, in turn, results in a more reproducible and efficient production.

Conventional methods of mass-production of drugs cannot fulfill all the key characteristics that affect the efficacy of pharmacotherapy. Considering that genetic factors and environmental conditions of the individual patient can affect the effectiveness of the therapy formulation of personalized medicines can successfully enhance the quality of life of the patients as well as reduce the risk of side effects. This is particularly important for the pediatric population due to the diversity of the group, especially because of the significant physical and developmental disparities between newborns and teenagers. Following the approval of the first 3D printed tablets by the U.S. Food and Drug Administration in 2015, 3D printing of drug formulations became a promising tool for preparing personalized medicines. Favorable price aspect, ability to manufacture drugs on a small scale, customization of dose, shape, and release profile have given 3D printing a great chance to revolutionize the pharmaceutical market. Fused Deposition Modeling (FDM) uses thermoplastic polymers forced through the printer nozzle at a temperature above melting or softening of the polymer filaments enabling an operator to control both the shape, size, and internal structure of the printed object. On the other hand, the biggest challenge for the implementation of this method in the pharmaceutical environment is the lack of commercially available pharmaceutical-grade filaments. To overcome such an obstacle a Hot-Melt Extrusion process (HME) can be applied providing drug-incorporated filaments of pharmaceutical quality. The findings indicate that FDM 3D printing coupled with HME is a feasible option for manufacturing new drug formulations in a variety of shapes and doses, and that this technique could advance the development of tailored pediatric medicines. This manuscript summarizes and addresses the current state of knowledge, as well as the critical aspects that must be considered, in order to expand the application of FDM 3D printing as a viable manufacturing option for pediatric drugs.

Electrospraying and electrospinning are electrohydrodynamic techniques that are applicable to the production of both capsules and fibers on a micro scale. Electrical forces are applied to the surface of the polymer solution to form a charged jet that stretches towards the collector with simultaneous solvent evaporation, forming beads (microcapsules) or microfibers with polymer coating; the morphology heavily influenced by the stability of the jet. These methods can be used to achieve carriers for biologically active hydrophobic substances, such as oils, fatty acids, and oil-soluble substances due to the fact that they do not require the use of high temperatures or toxic solvents. They enable the encapsulation of liquids in polymeric structures and limit possible oxidative degeneration of sensitive compounds. A potential application for electrosprayed microcapsules and electrospun microfibers is functional food production. Careful selection of polymers of various sources and solvents, as well as process parameters, allows for sealing the oil in the shell. The obtained products show more favorable properties in comparison with oils in the bulk, as well as capsules produced using other common encapsulation techniques. Several properties of the solutions such as their viscosity, surface tension, conductivity, and the degree of polymer chain entanglement directly influence bead or fiber formation. One of the strategies for encapsulation of oils is to disperse it in the polymer solution and use the obtained w/o emulsion as the spraying liquid. Multiple emitters are also used, in the so-called coaxial (or multiaxial) electrospraying/electrospinning. This review discusses the fundamental principles of the electrohydrodynamic processes, as well as various parameters of those techniques (related to solution properties, polymer and solvent selection, the equipment used, and the methods applied to product analysis in terms of its morphology, encapsulation efficiency, and oxidation).

Cocrystals can be defined as crystalline solids composed of at least two compounds in a stoichiometric ratio which interact nonionically. While one of the components is an active pharmaceutical ingredient (API) the term ‘pharmaceutical cocrystal’ could be applied. These are the subject of interest in academic and industrial research as they offer better control over physicochemical, mechanical and pharmacokinetic properties of API while its therapeutic activity remains intact. Commercial success of this approach can be confirmed by the number of marketed pharmaceutical cocrystal drug forms. Despite the range of cocrystallization methods introduced, it is challenging to propose a technique meeting industrial requirements such as scalability or continuousness of the process with respect to ‘green chemistry’ principles being reduction of solvents use. This paper covers the criteria of cocrystallization method selection and presents techniques potentially applicable for large-scale purposes such as Hot Melt Extrusion, Matrix Assisted Cocrystallization and spray congealing with advantages and limitations of those. Within mechanochemical methods of obtaining cocrystals, Matrix Assisted Cocrystallization (MAC) is a promising candidate for industrial-scale use as it is a continuous, one-step, solvent-free technique offering high control over process parameters (e.g. temperature, feed rate, screw speed, screw configuration, extruder type) in order to increase the efficiency of the synthesis and provide high quality product. The addition of polymer facilitates the extrusion and enables conducting the process at lower temperature to prevent degradation of thermolabile substances. Furthermore, cocrystals embedded in polymeric matrix can exhibit the improvement of dissolution rate or compressibility. Additionally, the MAC can be coupled with Process Analytical Technology (PAT) tools to provide real-time data for manufacturing process monitoring and control of product quality.

Control over polymorphism and solvatomorphism in API assisted by structural information, e.g., molecular conformation or associations via hydrogen bonds, is crucial for the industrial development of new drugs, as the crystallization products differ in solubility, dissolution profile, compressibility, or melting temperature. The stability of the final formulation and technological factors of the pharmaceutical powders further emphasize the importance of precise crystallization protocols. This is particularly important when working with highly flexible molecules with considerable conformational freedom and a large number of hydrogen bond donors or acceptors (e.g., fluconazole, FLU). Here, cooling and suspension crystallization were applied to access polymorphs and solvates of FLU, a widely used azole antifungal agent with high molecular flexibility and several reported polymorphs. Each of four polymorphic forms, FLU I, II, III, or IV, can be obtained from the same set of alcohols (MeOH, EtOH, isPrOH) and DMF via careful control of the crystallization conditions. For the first time, two types of isostructural channel solvates of FLU were obtained (nine new structures). Type I solvates were prepared by cooling crystallization in Tol, ACN, DMSO, BuOH, and BuON. Type II solvates formed in DCM, ACN, nPrOH, and BuOH during suspension experiments. We propose desolvation pathways for both types of solvates based on the structural analysis of the newly obtained solvates and their desolvation products. Type I solvates desolvate to FLU form I by hydrogen-bonded chain rearrangements. Type II solvates desolvation leads first to an isomorphic desolvate, followed by a phase transition to FLU form II through hydrogen-bonded dimer rearrangement. Combining solvent-mediated phase transformations with structural analysis and solid-state NMR, supported by periodic electronic structure calculations, allowed us to elucidate the interrelations and transformation pathways of FLU.

Background: The aim of the study was to compare the effectiveness of photodynamic therapy (PDT) to steroid therapy in the treatment of oral lichen planus (OLP). Due to the lack of commercially available drug carriers, innovative proprietary solutions were used for both the photosensitiser and the steroid carrier—in the first case to shorten and in the second to extend the contact of the active substance with the mucosa. Methods: A prospective, randomised, single-blind, 12-week full contralateral split-mouth clinical trial of 30 patients with bilateral oral lichen planus was conducted. The prepared matrices were incorporated with active substances methylene blue 5% and 0,05% triamcinolone. The size of lesions, Thongprasom, ABISIS, and VAS scale were evaluated. Results: Relatively high rates of complete remission of lichen were demonstrated: immediately after treatment, 33.3% with PDT and 22.2% with triamcinolone (TA), and after 3 months, 54.2% with PDT and 62.9% with TA. After 3 months of treatment, a reduction in the area of evaluated lesions of 52.7% for PDT and 41.7% for TA was achieved. Conclusion: In situations of topical or general contraindications to oral corticosteroids, resistance to them, or the need for repeated treatment in a short period of time, PDT appears to be a very promising treatment option.

Increasing access to additive manufacturing technologies utilising easily available desktop devices opened novel ways for formulation of personalized medicines. It is, however, challenging to propose a flexible and robust formulation platform which can be used for fabrication of tailored solid dosage forms composed of APIs with different properties (e.g., hydrophobicity) without extensive optimization. This manuscript presents a strategy for formulation of fast dissolving tablets using binder jetting (BJ) technology. The approach is demonstrated using two model APIs: hydrophilic quinapril hydrochloride (QHCl, logP = 1.4) and hydrophobic clotrimazole (CLO, logP = 5.4). The proposed printing method uses inexpensive well known and easily available FDA approved pharmaceutical excipients. The obtained model tablets had uniform content of the drug, excellent mechanical properties and highly porous structure resulting in short disintegration time and fast dissolution rate. The tablets could be scaled and obtained in predesigned shapes and sizes. The proposed method may find its application in the early stages of drug development where high flexibility of the formulation is required and the amount of available API is limited.

In order to overcome the limitations associated with vaginal administration of drugs, e.g., the short contact time of the drug form with the mucosa or continuous carrier wash-out, the development of new carriers for gynecological use is necessary. Furthermore, high individual anatomical and physiological variability resulting in unsatisfactory therapeutic efficacy of lipophilic active substances requires application of multicompartment drug delivery systems. This manuscript provides an up-to-date comprehensive review of the literature on emulsion-based vaginal dosage forms (EVDF) including macroemulsions, microemulsions, nanoemulsions, multiple emulsions and self-emulsifying drug delivery systems. The first part of the paper discusses (i) the influence of anatomical-physiological conditions on therapeutic efficacy of drug forms after local and systemic administration, (ii) characterization of EVDF components and the manufacturing techniques of these dosage forms and (iii) methods used to evaluate the physicochemical and pharmaceutical properties of emulsion-based vaginal dosage forms. The second part of the paper presents (iv) the results of biological and in vivo studies as well as (v) clinical evaluation of EVDF safety and therapeutic efficacy across different indications.

Acyclovir, an antiviral purine derivative listed on the WHO's Model List of Essential Medicines, is commonly used in several different dosage forms from tablets to gels, oleogels and suspensions. Although temperature driven phase transitions of its commercially available 3 : 2 hydrate have been known since 2011, information on the solvent driven phase transitions of this drug has been limited. This study identifies the pathways of transformations of acyclovir forms I and V induced by organic solvents and water using the method of solution mediated phase transformation. The 3 : 2 hydrate, form V, undergoes dehydration to anhydrous form I in methanol, ethanol and N,N-dimethylformamide. Form I converts to anhydrous form II in dry methanol and N,N-dimethylformamide, while increased water content in the solvent prevents the transformation of form I to form II. Both forms I and V yield a gel-like material in dimethyl sulfoxide, composed of highly crystalline form II and reported here for the first time. Furthermore, significant differences in the thermal dehydration process of forms V and VI were observed using VT FTIR, including the first time report on a novel metastable ACV form VII formed upon dehydration of ACV dihydrate (form VI). High resolution solid-state NMR spectra of two anhydrous polymorphs (forms I and II) and two hydrates (forms V and VI) supported by DFT calculations using the CASTEP code are also presented.

Experimental screening for new crystalline forms of a flavan-3-ol derivative, catechin, yielded several new solvates and solvate-hydrates of this polyphenol, among which a new methanol-containing crystalline solid was identified. This form was found to be different from the previously described 2 : 1 methanol solvate of catechin. It contains one molecule of water and 0.5 molecules of methanol per catechin molecule in the asymmetric unit. To determine the crystal structure of this form, NMR crystallography and crystal structure prediction (CSP) calculations were used, as every attempt to obtain a single crystal of sufficient quality to perform single crystal X-ray diffraction failed. To deal with a system containing five independent components in the CSP search (due to the necessity of treating whole molecules), in addition to the intramolecular flexibility of catechin with 68 viable conformers, we developed a useful short-cut, which allows for limiting the number of conformations considered in such demanding calculations. In this work, we show that it is possible to use the simulated NMR data for CSP-generated crystal structures of a simpler, yet similar system, to indicate the likely molecular conformation present in a more complex system. This approach allowed us to determine the experimental crystal structure of catechin methanol hemisolvate-monohydrate. This journal is

Encapsulation of pharmaceuticals inside nanoporous materials is of increasing interest due to their possible applications as new generation therapeutics, theranostic platforms, or smart devices. Mesoporous silicas are leading materials to be used as nanohosts for pharmaceuticals. Further development of new generation of nanoscale therapeutics requires complete understanding of the complex host-guest interactions of organic molecules confined in nanosized chambers at different length scales. In this context, we present results showing control over formation and phase transition of nanosize crystals of model flexible pharmaceutical molecule tolbutamide confined inside 3.2 nm pores of the MCM-41 host. Using low loading levels (up to 30 wt %), we were able to stabilize the drug in highly dynamic amorphous/disordered state or direct the crystallization of the drug into highly metastable nanocrystalline form V of tolbutamide (at loading levels of 40 and 50 wt %), providing first experimental evidence for crystallization of pharmaceuticals inside the pores as narrow as 3.2 nm.

Phenylalanine is an important amino acid both biologically, essential to human health, and industrially, as a building block of artificial sweeteners. Our interest in this particular amino acid and its derivatives lies with its ability to form gels in a number of solvents. We present here the studies of the influence of halogen addition to the aromatic ring on the gelation properties and we analyse the crystal structures of a number of these materials to elucidate the trends in their behaviour based on the halogen addition to the aromatic group and the interactions that result.

Use of hot melt extrusion (HME) as continuous manufacturing process in the cocrystal synthesis is of increasing interest from both industrial and academic perspective and it is seen as a newly developing branch of mechanochemistry with possible broad application in single step synthesis and formulation of pharmaceutical cocrystals. Furthermore, one-step formulation of pharmaceutical products results in combined processing of pharmaceutical cocrystal mixtures with polymers using HME, which may result in phase change or formation of amorphous solid dispersions during the material processing. The manuscript aims at providing selection guidelines and understanding of processing parameters and instrumental setup of importance to design the HME process for cocrystal synthesis. Furthermore, importance of stoichiometry control of the final product and the matrix selection criteria in simultaneous synthesis and formulation of pharmaceutical cocrystals via HME are provided. The first part of this review, introduce mechanochemical methods of cocrystals synthesis along brief explanation of the possible molecular mechanisms of cocrystal synthesis via mechanochemical approach. Subsequently, the critical process parameters i.e. temperature, screw speed, screw configuration or material feed rate of importance in successful synthesis of high quality product are described followed by literature examples of the processing of neat cocrystal compounds or matrix assisted cocrystallisation.

The introduction of fluorine into the structure of pharmaceuticals has been an effective strategy for tuning their pharmacodynamic properties, with more than 40 new drugs entering the market in the last 15 years. In this context, (19) F NMR spectroscopy can be viewed as a useful method for investigating the host-guest chemistry of pharmaceuticals in nanosized drug-delivery systems. Although the interest in confined crystallization, nanosized devices, and porous catalysts is gradually increasing, understanding of the complex phase behavior of organic molecules confined within nanochambers or nanoreactors is still lacking. Using (19) F magic-angle-spinning NMR spectroscopy, we obtained detailed mechanistic insight into the crystallization of flufenamic acid (FFA) in a confined environment of mesoporous silica materials with different pore diameters (3.2-29 nm), providing direct experimental evidence for the formation of a molecular-liquid-like layer besides crystalline confined FFA form I.

Introduction of fluorine in the structure of pharmaceuticals has been an effective strategy for tuning their pharmacodynamic properties with more than 40 new drugs accessing the market in last 15 years. In this context 19F NMR can be viewed as a useful probe for investigating the host-guest chemistry of pharmaceuticals in nanosize drug delivery systems. Although the interest in confined crystallisation, nanosize devices and porous catalysts is gradually increasing, understanding of the complex phase behavior of organic molecules confined within nano-chambers or nano-reactors is still lacking. Using 19F MAS NMR, we achieved detailed mechanistic insight into the crystallization of flufenamic acid (FFA) in a confined environment of mesoporous silicas with different pore diameters (3.2 to 29 nm), providing a direct experimental proof of the formation of a molecular liquid-like layer in addition to the crystalline confined FFA form I.

Polymer-assisted cocrystallisation via hot melt extrusion (HME) facilitates the cocrystallisation process and increases cocrystal yield compared with the HME of neat cocrystal components. This makes it an attractive method for the single-step continuous synthesis of pharmaceutical cocrystals. The aim of this study is to understand the effect of semicrystalline (Poloxamer P407, PXM) or amorphous (Soluplus®, SOL) polymers on the cocrystallisation of model theophylline-nicotinamide (TP:NA, 1:1) cocrystal with significantly different melting temperatures of API (TP, m.p. = 271.4 °C) and coformer (NA, m.p. = 128.7 °C) in neat and matrix-assisted cocrystallisation via HME. Compared with the processing of neat cocrystal components, the addition of PXM led to formulation of TP:NA cocrystal embedded in the polymer matrix and increased the cocrystal formation efficiency. On the other hand, the co-processing of cocrystal components with SOL resulted in the formation of cocrystal embedded in the amorphous polymer matrix or in the partially amorphous TP:NA/SOL composites. The one-step formulation of API:coformer mixtures with polymers using HME may result in phase changes or the formation of amorphous solid dispersions, which highlights the importance of matrix selection and phase control of the final product.

Solid-state synthesis of pharmaceutical cocrystals is of contemporary interest as it offers an efficient way to modify the physicochemical properties of Active Pharmaceutical Ingredient (API) including its melting point, solubility, compressibility or physical stability, without compromising its structural integrity and bioactivity. Therefore, research of novel and emerging techniques for solvent-free, continuous and scalable methods for cocrystal formation is of paramount importance for further industrial development. In this work we form a basis for knowledge-based synthesis and formulation of model pharmaceutical cocrystal (flufenamic acid, FFA: nicotinamide, NA; 1:1) via matrix-assisted cocrystallisation (MAC) using Hot Melt Extrusion (HME). Five different polymers frequently used in pharmaceutical drug delivery: Poloxamer P407 (PXM), PEG-PVA copolymer, Soluplus® (SOL), PVPVA64 and HPMCAS with different structural features and physicochemical properties were investigated as functional matrices for FFA:NA cocrystal synthesis via HME. Significant decrease of the torque value during MAC process was observed for all investigated polymers as compared to extrusion of neat FFA:NA cocrystal. The FFA:NA cocrystal encapsulated in the polymer matrix was successfully formed using semicrystalline PXM and PEG-PVA polymers at all investigated FFA:NA/polymer ratios. The use of amorphous polymers (SOL, PVPVA64, HPMCAS) as a cocrystallisation matrix resulted in formation of FFA:NA cocrystal embedded in an amorphous FFA:NA/polymer matrix (at polymer contents of 10 and 20 wt.%) or FFA:NA/polymer amorphous composites at SOL and PVPVA64 content of 30 wt.%. Furthermore, the significant increase of FFA dissolution was observed for FFA:NA cocrystal encapsulated in PXM and PEG-PVA matrices as compared to neat FFA form I. FFA form III and FFA:NA cocrystal. The presented work enables for the first time knowledge-based approach for simultaneous synthesis and formulation of pharmaceutical cocrystals via Hot Melt Extrusion a solvent-free, scalable and continuous process.

Phenylalanine (Phe) is an amino acid of great interest as coupling of an aromatic group with a chiral hydrophilic region imparts a number of unique properties. Recently there has been an increased interest in the crystalline and gel forms of this compound, part as a result of the complex and undetermined structures of the resulting materials and the relationship of the solid forms of Phe with the disease phenylketonuria. In this report, we highlight the relationship between gelation, crystallization, and the dynamics of self-assembly processes of Phe. We do this by describing the gelation of the amino acid, the gel to crystal relationship, crystal structure predictions for this relatively simple compound, and the dynamics of assembly as determined by NMR in both water and dimethyl sulfoxide. This will provide guidance to future research into Phe assemblies, possible treatments for phenylketonuria, and diseases related to formation of amyloid-like fibers.

Supramolecular hydrogels are composed of self‐assembled solid networks that restrict the flow of water. l‐Phenylalanine is the smallest molecule reported to date to form gel networks in water, and it is of particular interest due to its crystalline gel state. Single and multi‐component hydrogels of l‐phenylalanine are used herein as model materials to develop an NMR‐based analytical approach to gain insight into the mechanisms of supramolecular gelation. Structure and composition of the gel fibres were probed using PXRD, solid‐state NMR experiments and microscopic techniques. Solution‐state NMR studies probed the properties of free gelator molecules in an equilibrium with bound molecules. The dynamics of exchange at the gel/solution interfaces was investigated further using high‐resolution magic angle spinning (HR‐MAS) and saturation transfer difference (STD) NMR experiments. This approach allowed the identification of which additive molecules contributed in modifying the material properties.

This study aims at investigating the molecular level organization and molecular mobility in montmorillonite nanocomposites with the uncharged organic low-molecular-weight compound lactose commonly used in pharmaceutical drug delivery, food technology, and flavoring. Nanocomposites were prepared under slow and fast drying conditions, attained by drying at ambient conditions and by spray-drying, respectively. A detailed structural investigation was performed with modulated differential scanning calorimetry, powder X-ray diffraction, solid-state nuclear magnetic resonance spectroscopy, scanning electron microscopy, microcalorimetry, and molecular dynamics simulations. The lactose was intercalated in the sodium montmorillonite interlayer space regardless of the clay content, drying rate, or humidity exposure. Although, the spray-drying resulted in higher proportion of intercalated lactose compared with the drying under ambient conditions, nonintercalated lactose was present at 20 wt % lactose content and above. This indicates limitations in maximum loading capacity of nonionic organic substances into the montmorillonite interlayer space. Furthermore, a fraction of the intercalated lactose in the co-spray-dried nanocomposites diffused out from the clay interlayer space upon humidity exposure. Also, the lactose in the nanocomposites demonstrated higher molecular mobility than that of neat amorphous lactose. This study provides a foundation for understanding functional properties of lactose/Na-MMT nanocomposites, such as loading capacity and physical stability.

Actinomycetes, such as mycobacteria and streptomycetes, synthesize α-glucan with α-1,4 linkages and α-1,6 branching to help evade immune responses and to store carbon. α-Glucan is thought to resemble glycogen except for having shorter constituent linear chains. However, the fine structure of α-glucan and how it can be defined by the maltosyl transferase GlgE and branching enzyme GlgB were not known. Using a combination of enzymolysis and mass spectrometry, we compared the properties of α-glucan isolated from actinomycetes with polymer synthesized in vitro by GlgE and GlgB. We now propose the following assembly mechanism. Polymer synthesis starts with GlgE and its donor substrate, α-maltose 1-phosphate, yielding a linear oligomer with a degree of polymerization (∼16) sufficient for GlgB to introduce a branch. Branching involves strictly intrachain transfer to generate a C chain (the only constituent chain to retain its reducing end), which now bears an A chain (a nonreducing end terminal branch that does not itself bear a branch). GlgE preferentially extends A chains allowing GlgB to act iteratively to generate new A chains emanating from B chains (nonterminal branches that themselves bear a branch). Although extension and branching occur primarily with A chains, the other chain types are sometimes extended and branched such that some B chains (and possibly C chains) bear more than one branch. This occurs less frequently in α-glucans than in classical glycogens. The very similar properties of cytosolic and capsular α-glucans from Mycobacterium tuberculosis imply GlgE and GlgB are sufficient to synthesize them both.

It has previously been reported that the caffeine : malonic acid co-crystal system forms spontaneously upon the contact of the two materials. Here we studied the crystal growth in this system to rationally define the role that water plays, thus enabling us to monitor the conversion by solid-state NMR and control the kinetics of spontaneous co-crystal production by increasing or decreasing the relative humidity.

Orotic acid (OTA) is reported to exist in the anhydrous (AH), monohydrate (Hy1), and dimethyl sulfoxide monosolvate (SDMSO) forms. In this study we investigate the (de)hydration/desolvation behavior, aiming at an understanding of the elusive structural features of anhydrous OTA by a combination of experimental and computational techniques, namely, thermal analytical methods, gravimetric moisture (de)sorption studies, water activity measurements, X-ray powder diffraction, spectroscopy (vibrational, solid-state NMR), crystal energy landscape, and chemical shift calculations. The Hy1 is a highly stable hydrate, which dissociates above 135 °C and loses only a small part of the water when stored over desiccants (25 °C) for more than one year. In Hy1, orotic acid and water molecules are linked by strong hydrogen bonds in nearly perfectly planar arranged stacked layers. The layers are spaced by 3.1 Å and not linked via hydrogen bonds. Upon dehydration the X-ray powder diffraction and solid-state NMR peaks become broader, indicating some disorder in the anhydrous form. The Hy1 stacking reflection (122) is maintained, suggesting that the OTA molecules are still arranged in stacked layers in the dehydration product. Desolvation of SDMSO, a nonlayer structure, results in the same AH phase as observed upon dehydrating Hy1. Depending on the desolvation conditions, different levels of order–disorder of layers present in anhydrous OTA are observed, which is also suggested by the computed low energy crystal structures. These structures provide models for stacking faults as intergrowth of different layers is possible. The variability in anhydrate crystals is of practical concern as it affects the moisture dependent stability of AH with respect to hydration.

The dissolution rate of anhydrous acyclovir was improved by the preparation of physical mixtures and solid dispersions with the non-ionic polymer Pluronic F127 using the kneading method at different drug-to-polymer ratios. The obtained physical mixtures and solid dispersions were examined in terms of drug content and possible physical and chemical interactions between the drug and polymer using FTIR spectral studies, differential scanning calorimetry and powder X-ray diffraction analysis. The dissolution rate of acyclovir was determined using the rotating disk method. It was found that the minimal content of the polymer within the mixtures needed to increase the dissolution rate of the drug was 50 %.

The nanocrystallisation of complex molecules inside mesoporous hosts and control over the resulting structure is a significant challenge. To date the largest organic molecule crystallised inside the nano-pores is a known pharmaceutical intermediate - ROY (259.3 g mol(-1)). In this work we demonstrate smart manipulation of the phase of a larger confined pharmaceutical - indomethacin (IMC, 357.8 g mol(-1)), a substance with known conformational flexibility and complex polymorphic behaviour. We show the detailed structural analysis and the control of solid state transformations of encapsulated molecules inside the pores of mesoscopic cellular foam (MCF, pore size ca. 29 nm) and controlled pore glass (CPG, pore size ca. 55 nm). Starting from confined amorphous IMC we drive crystallisation into a confined methanol solvate, which upon vacuum drying leads to the stabilised rare form V of IMC inside the MCF host. In contrast to the pure form, encapsulated form V does not transform into a more stable polymorph upon heating. The size of the constraining pores and the drug concentration within the pores determine whether the amorphous state of the drug is stabilised or it recrystallises into confined nanocrystals. The work presents, in a critical manner, an application of complementary techniques (DSC, PXRD, solid-state NMR, N2 adsorption) to confirm unambiguously the phase transitions under confinement and offers a comprehensive strategy towards the formation and control of nano-crystalline encapsulated organic solids.

Background Modern anticancer chemotherapy can cause numerous adverse effects in the organism, whose functioning has already been disrupted by the neoplastic process itself. Objectives The aim of the study was to evaluate and compare the frequency and severity of the toxicity of FOLFOX-4 and CLF-1 anticancer therapy in patients with colon cancer, and to analyze certain factors that might have increased the toxicity of the chemotherapy. Material and methods The study involved 64 patients suffering from generalized colon cancer, including 48 patients treated according to the FOLFOX-4 regimen and 16 patients treated according to the CLF-1 regimen. The toxicity of each regimen was analyzed on the basis of a confidential questionnaire formulated by the authors and laboratory research according to the extended WHO toxicity criteria. Results The analysis of the symptoms of toxicity symptoms associated with the use of the FOLFOX-4 and CLF-1 therapeutic regimens revealed that the most common side effects included nausea and vomiting, despite ondansetron premedication, and neurotoxicity. Disruption of the functioning of the nervous system under the FOLFOX-4 regimen statistically significant exacerbation that increased with the number of chemotherapy cycles administered; this was more common and more severe in women. Paresthesia was also revealed to be a neurotoxic effect of the FOLFOX-4 regimen after termination of therapy. A statistically significant relationship was observed between the use of vitamin supplements and the incidence and severity of the toxicity of the FOLFOX-4 regimen. Conclusions The findings of the current study regarding the toxicity of the FOLFOX-4 and CLF-1 therapy regimens should be taken into consideration when monitoring chemotherapy safety in colon cancer. The patients' tolerance of the administered medication and the side effects reported by patients should be constantly evaluated, which will help prevent these side effects, apply appropriate therapy and contribute to the improvement of the patients' quality of life. The functioning of the central nervous system should be carefully evaluated when planning the anticancer therapy, especially if repeated administration of neurotoxic drugs is necessary in cases of a recurrence of the disease. Chemotherapy should be thoroughly monitored for safety, especially in women over 65 years of age suffering from coexisting diseases. Colon cancer patients and their families should be informed of the risks of nutritional supplements before the start of the anticancer chemotherapy, and may need to dispense with their use.