Exploring Immersion Coating as a Cost-Effective Method for Small-Scale Production of Enteric-Coated Gelatin Capsules.

The coating process for solid dosage forms is widely used in the pharmaceutical industry but presents challenges for small-scale production, needed in personalized medicine and clinical or galenic settings. This study aimed to evaluate immersion coating, a cost-effective small-scale method, for enteric-coated gelatin capsules using standard equipment. Two enteric coating polymers and different polymer concentrations were tested, along with API solubility. Results were compared with commercially available enteric capsule shells. Successful preparation of enteric coating capsules via immersion necessitates a comprehensive grasp of API and enteric polymer behavior. However, utilizing commercially available enteric capsule shells does not guarantee ease or robustness, as their efficacy hinges on the attributes of the active ingredient and excipients. Notably, coating with Eudragit S100 stands out for its superior process robustness, requiring minimal or no development time, thus representing the best option for small-scale enteric capsule production.

Hydrogel containing mPEG-PLGA nanoparticles for the vaginal delivery of saquinavir mesylate against HIV infection.

Saquinavir mesylate (SQV) is a protease inhibitor commonly employed for the treatment of human immunodeficiency virus-1 infection. It is generally administered orally as tablets in combination with other antiviral drugs. Another promising route of administration can be represented by the vaginal one through topically applied formulations. This delivery can reduce the first-pass effect in the case of systemic drug adsorption or prevent HIV infection. We propose the formulation of a Carbopol® 974 (C974) hydrogel containing biodegradable mPEG-PL(L)GA nanoparticles (NPs) for the vaginal delivery of SQV, intended both as a prevention and a therapeutic strategy. mPEG-PL(L)GA NPs were incorporated into the C974 polymeric matrix, leading to a reduction of the hydrogel consistency dependent on NPs and C974 concentrations. Despite the moderate drug loading into NPs, the presence of the NPs had an impact on the in vitro release of the drug from the hydrogel at pH 5.5 using immersion cells. A higher amount of the drug was released, probably due to the effect of NPs in promoting the incorporation of the drug into the hydrogel at a high SQV dose. These findings can be useful for the development of topically applied hydrogels for SQV delivery, possibly having improved in vivo therapeutic outcomes.

High-Resolution Ultrasound Spectroscopy for the Determination of Phospholipid Transitions in Liposomal Dispersions.

High-resolution ultrasound spectroscopy (HR-US) is a spectroscopic technique using ultrasound waves at high frequencies to investigate the structural properties of dispersed materials. This technique is able to monitor the variation of ultrasound parameters (sound speed and attenuation) due to the interaction of ultrasound waves with samples as a function of temperature and concentration. Despite being employed for the characterization of several colloidal systems, there is a lack in the literature regarding the comparison between the potential of HR-US for the determination of phospholipid thermal transitions and that of other common techniques both for loaded or unloaded liposomes. Thermal transitions of liposomes composed of pure phospholipids (dimyristoylphosphatidylcholine, DMPC; dipalmitoylphosphatidylcholine, DPPC and distearoylphosphatidylcholine, DSPC), cholesterol and their mixtures were investigated by HR-US in comparison to the most commonly employed microcalorimetry (mDSC) and dynamic light scattering (DLS). Moreover, tramadol hydrochloride, caffeine or miconazole nitrate as model drugs were loaded in DPPC liposomes to study the effect of their incorporation on thermal properties of a phospholipid bilayer. HR-US provided the determination of phospholipid sol-gel transition temperatures from both attenuation and sound speed that are comparable to those calculated by mDSC and DLS techniques for all analysed liposomal dispersions, both loaded and unloaded. Therefore, HR-US is proposed here as an alternative technique to determine the transition temperature of phospholipid membrane in liposomes.

Antioxidant Properties of Ester Derivatives of Cinnamic and Hydroxycinnamic Acids in Nigella sativa and Extra-Virgin Olive Oils-Based Emulsions.

New hydrophobic derivatives of cinnamic and hydroxycinnamic (ferulic and cumaric) acids obtained by chemical esterification of the carboxylic group with C10 linear alcohol were studied to evaluate their antioxidant capacity toward the superoxide anion and hydrogen peroxide in physiological buffer and in extra-virgin olive oil (EVO) or Nigella sativa oils. Results showed that cumaric and ferulic acids have higher antioxidants activity against superoxide anion and hydrogen peroxide than the other compounds. Cumaric acid and its C10-ester derivative were selected to be incorporated into EVO or Nigella sativa oil-based emulsions. The prepared emulsions had a comparable particle size distribution (in the range of 3-4 µm) and physical stability at least up to three months. Nigella sativa oil-based emulsions loaded with cumaric acid or its C10-ester showed a higher capacity to scavenger superoxide anion and hydrogen peroxide than EVO oil-based emulsions. In conclusion, cumaric acid or its C10-ester could promote the antioxidant properties of Nigella sativa oil when formulated as emulsions.

Factors affecting the rheological behaviour of carbomer dispersions in hydroalcoholic medium: Towards the optimization of hand sanitiser gel formulations.

Hand sanitizers represent a primary measure for the prevention of transmissible infections, whose use has been greatly increased during CoViD-19 pandemic. Most of the commercially available products are hydrogels, employing carbomers as thickening agents. However, few information is still available regarding performances of carbomers in hydroalcoholic media containing a percentage of alcohols ≥ 60% v/v as recommended for disinfection. The aim of this study was to investigate the colloidal behaviour of carbomer 974 and carbomer 980 in hydroalcoholic media containing from 50 to 80% w/w of alcohol (ethanol or isopropanol) and neutralised with triethanolamine or aminomethyl propanol. Both carbomers provide transparent hydrogels in water, but carbomer 980 should be preferred for the formulation of hydrogel with a percentage of alcohol ≥ 50% w/w for its better solvation. The critical alcohol concentration (CAlC), above which polymer precipitation occurs, depends on the type of alcohol and base used. Carbomer dispersions with a higher content of alcohol can be prepared using aminomethyl propanol rather than triethanolamine. The choice of the more suitable components is fundamental for the isopropanol-based dispersions since the CAlC is closer to the recommended concentrations for disinfection. Overall, these results provide helpful insights for the correct preparation of alcohol-based hand sanitizers using carbomers.

A Design of Experiment (DoE) Approach to Model the Yield and Chemical Composition of Ajowan (Trachyspermum ammi L.) Essential Oil Obtained by Microwave-Assisted Extraction.

Ajowan (Trachyspermum ammi L.) is a spice traditionally used in Middle Eastern medicine and contains a valuable essential oil (EO) exploited in different fields, such as pharmaceutics, agrochemicals and food additives. This EO is mostly characterized by the thymol to which most of its biological properties are related. Given the economic value of ajowan and its increasing demand across the globe, the extraction method used for its EO is of paramount importance in terms of quality and quantity of the final product. In the present study, we used the design of experiment (DoE) approach to study and optimize the extraction of the ajowan EO using the microwave-assisted extraction (MAE), a novel extraction technique with high efficiency, low energy consumption, short process length and low environmental impact. A two-step DoE (screening followed by surface response methodology) was used to reduce the number of experiments and to improve the cost/benefit ratio. Reliable mathematical models, relating the more relevant EO features with the extraction conditions, were obtained and used to identify the best experimental conditions able to maximize the yield and thymol concentration. The optimized MAE procedure assures an EO with a higher yield and thymol amount compared with the standard hydrodistillation procedure.

Encapsulation of Flavours and Fragrances into Polymeric Capsules and Cyclodextrins Inclusion Complexes: An Update.

Flavours and fragrances are volatile compounds of large interest for different applications. Due to their high tendency of evaporation and, in most cases, poor chemical stability, these compounds need to be encapsulated for handling and industrial processing. Encapsulation, indeed, resulted in being effective at overcoming the main concerns related to volatile compound manipulation, and several industrial products contain flavours and fragrances in an encapsulated form for the final usage of customers. Although several organic or inorganic materials have been investigated for the production of coated micro- or nanosystems intended for the encapsulation of fragrances and flavours, polymeric coating, leading to the formation of micro- or nanocapsules with a core-shell architecture, as well as a molecular inclusion complexation with cyclodextrins, are still the most used. The present review aims to summarise the recent literature about the encapsulation of fragrances and flavours into polymeric micro- or nanocapsules or inclusion complexes with cyclodextrins, with a focus on methods for micro/nanoencapsulation and applications in the different technological fields, including the textile, cosmetic, food and paper industries.

Surfactant Self-Assembling and Critical Micelle Concentration: One Approach Fits All?

Critical micelle concentration (CMC) is the main chemical-physical parameter to be determined for pure surfactants for their characterization in terms of surface activity and self-assembled aggregation. The CMC values can be calculated from different techniques (e.g., tensiometry, conductivity, fluorescence spectroscopy), able to follow the variation of a physical property with surfactant concentrations. Different mathematical approaches have been applied for the determination of CMC values from the raw experimental data. Most of them are independent of the operator, despite not all of the fitting procedures employed so far can be applied in all techniques. In this experimental work, the second derivative of the experimental data has been proposed as a unique approach to determine the CMC values from different techniques (tensiometry, conductimetry, densimetry, spectrofluorimetry, and high-resolution ultrasound spectroscopy). To this end, the CMC values of five different surfactants, specifically three anionic (sodium dodecyl sulfate, sodium deoxycolate, and N-lauroyl sarcosinate) and two nonionic, such as polyethylene glycol ester surfactants [polyethylenglicol (8) monostearate and polyethylenglicol (8) monolaurate], have been determined by this approach. The "second-derivate" approach provides a reliable determination of the CMC values among all of the techniques investigated, which were comparable to those calculated by the other operator-free routinely methods employed, such as segmental linear regression or Boltzmann regression. This study also highlighted the strengths and shortcomings of each technique over the others, providing an overview of the CMC values of commonly used anionic and nonionic surfactants in the pharmaceutical field, determined by employing different experimental approaches.

3D-printed microfluidic chip for the preparation of glycyrrhetinic acid-loaded ethanolic liposomes.

18-α-Glycyrrhetinic acid (GA) is a bioactive compound extracted from licorice that exhibits many biological and pharmacological effects such as anti-inflammatory and antioxidant activities on the skin. However, its lipophilic nature results in poor bioavailability that limits clinical applications. Liposomes, presenting the ability to carry both hydrophobic and hydrophilic payloads and a good cytocompatibility, are effective to overcome this barrier. Furthermore, the addition of permeation enhancers such as ethanol into liposomal formulations helps the diffusion of these systems through the skin barrier. Here, we aimed to formulate GA-loaded ethanolic liposomes, using a natural soybean lecithin via a microfluidic approach. Using a fused deposition modeling (FDM) 3D printer we customized a microfluidic chip, and manufactured vesicles that presented spherical shape with a size of 202 ± 5.2 nm, a narrow size distribution and a good stability over a period of 30 days. After reaching a drug encapsulation efficiency of 63.15 ± 2.2%, liposomes were evaluated for their cytocompatibility and skin permeation potentiality after hydrogelation using xanthan gum. The in vitro release and permeation studies were performed using Franz diffusion cells comparing two different media and three synthetic membranes including a polymeric skin-mimicking membrane. The selected formulation presented no cytotoxicity and an increased permeation compared to GA saturated hydrogel. It could perform therapeutically better effects than conventional formulations containing free GA, as prolonged and controlled release topical dosage forms, which may lead to improved efficiency and better patient compliance.

An Overview of Micro- and Nanoemulsions as Vehicles for Essential Oils: Formulation, Preparation and Stability.

The interest around essential oils is constantly increasing thanks to their biological properties exploitable in several fields, from pharmaceuticals to food and agriculture. However, their widespread use and marketing are still restricted due to their poor physico-chemical properties; i.e., high volatility, thermal decomposition, low water solubility, and stability issues. At the moment, the most suitable approach to overcome such limitations is based on the development of proper formulation strategies. One of the approaches suggested to achieve this goal is the so-called encapsulation process through the preparation of aqueous nano-dispersions. Among them, micro- and nanoemulsions are the most studied thanks to the ease of formulation, handling and to their manufacturing costs. In this direction, this review intends to offer an overview of the formulation, preparation and stability parameters of micro- and nanoemulsions. Specifically, recent literature has been examined in order to define the most common practices adopted (materials and fabrication methods), highlighting their suitability and effectiveness. Finally, relevant points related to formulations, such as optimization, characterization, stability and safety, not deeply studied or clarified yet, were discussed.

PEGylation affects the self-assembling behaviour of amphiphilic octapeptides.

Surfactant-like peptides are a class of amphiphilic macromolecules, which are able to self-assemble in water forming different supramolecular structures. Among them, octapeptides composed of six hydrophobic and two hydrophilic residues have attracted interest since they have a length similar to those of natural phospholipids. Supramolecular structures of different amphiphilic octapeptides have been widely reported, but no study has been performed aimed at investigating the effect of PEGylation on their self-assembling behaviour. The aim of the present work was to synthesize and characterise the self-assembling behaviour of PEGylated alanine- or valine based amphiphilic octapeptides (mPEG1.9kDa-DDAAAAAA and mPEG1.9kDa-DDVVVVVV) in comparison to the non-PEGylated ones (DDAAAAAA and DDVVVVVV). The self-aggregation process in ultrapure water was investigated by fluorescence spectroscopy, small angle neutron scattering (SANS), dynamic light scattering (DLS), while the secondary structure was assessed by circular dichroism. PEGylation markedly affects the self-assembling behaviour of these amphiphilic octapeptides in terms of both critical aggregation concentration (CAC) and shape of the formed supramolecular aggregates. Indeed, PEGylation increases CAC and prevents the self-aggregation into fibrillary supramolecular aggregates (as observed for non-PEGylated peptides), by promoting the formation of micelle-like structures (as demonstrated for valine-based octapeptide). On the other side, the secondary structure of peptides seems not to be affected by PEGylation. Overall, these results suggest that self-assembling behaviour of amphiphilic octapeptides can be modified by PEGylation, with a great potential impact for the future applications of these nanomaterials.

Quaternary Ammonium Leucine-Based Surfactants: The Effect of a Benzyl Group on Physicochemical Properties and Antimicrobial Activity.

Quaternary ammonium amphiphiles are a class of compounds with a wide range of commercial and industrial uses. In the pharmaceutical field, the most common quaternary ammonium surfactant is benzalkonium chloride (BAC), which is employed as a preservative in several topical formulations for ocular, skin, or nasal application. Despite the broad antimicrobial activity against Gram-positive and Gram-negative bacteria, as well as fungi and small enveloped viruses, safety concerns regarding its irritant and cytotoxic effect on epithelial cells still remain. In this work, quaternary ammonium derivatives of leucine esters (C10, C12 and C14) were synthesised as BAC analogues. These cationic surfactants were characterised in terms of critical micelle concentration (CMC, by tensiometry), cytotoxicity (MTS and LDH assays on the Caco-2 and Calu-3 cell lines) and antimicrobial activity on the bacterial species Staphylococcus aureus and Enterococcus faecalis among the Gram-positives, Escherichia coli and Pseudomonas aeruginosa among the Gram-negatives and the yeast Candida albicans. They showed satisfactory surface-active properties, and a cytotoxic effect that was dependent on the length of the hydrophobic chain. Lower minimum inhibiting concentration (MIC) values were calculated for C14-derivatives, which were comparable to those calculated for BAC toward Gram-positive bacteria and slightly higher for Gram-negative bacteria and C. albicans. Thus, the synthesised leucine-based quaternary ammonium cationic surfactants can potentially find application as promising surface-active compounds with antimicrobial activity.

The influence of core tablets rheology on the mechanical properties of press-coated tablets.

Press-coating (also called compression coating or dry coating) consists of a second compression of an outer layer of material over a preformed tablet core. Despite being old, this technology has returned to popularity due to its widespread use in preparation of chronotherapeutic dosage forms. The literature available on press-coated tablets has mainly investigated drug release kinetics, while there is a lack of information about their mechanical properties. Here we study, for the first time, the effect of material properties and manufacturing parameters on the mechanical characteristics of press-coated tablets. Firstly, we show that the stiffness of the bare core tablets depends on the material type and, in case of viscoelastic materials, also depends on the compression pressure. We then demonstrate that less stiff (i.e. more viscoelastic) core tablets deform to a greater extent upon the second compression and thus allow the formation of less porous, harder coats and with a more homogenous density distribution. Finally, we find that changes in the mechanical properties of press-coated tablets over one month storage are almost negligible. Our data suggest that viscoelastic rather than stiff cores should be used in dry coating, as they promote the formation of more homogenous coats and with better mechanical properties.

Effect of the concentration process on unloaded and doxorubicin loaded liposomal dispersions.

Liposomes are lamellar nanovesicles made of phospholipids of a great interest as drug delivery carriers, able to encapsulate both hydrophilic and lipophilic compounds. Some liposomal formulations have reached the market, including the doxorubicin loaded PEGylated liposomal dispersion Doxil®. The aim of the work was to investigate the possibility of concentrating liposomes through the ultrafiltration process under nitrogen pressure, using Doxil® formulation as a model. The concentrated liposomal dispersions (4x and 8x) obtained from Doxil® were characterised in terms of size evolution (dynamic light scattering), morphology (cryo-TEM) and thermal behaviour (microcalorimetry, mDSC and high-resolution ultrasonic spectroscopy, HR-US) and compared to the unloaded liposomes of the same composition. The ultrafiltration process resulted to be effective in concentrating both loaded and unloaded liposomal dispersions, which showed a particle size and thermal properties comparable to those of the non concentrated ones. Moreover, all liposomal dispersions did not show any remarkable variation in term of particle size distribution and morphology for at least 8 weeks after concentration. Altogether, results demonstrated the effectiveness in using ultrafiltration as a methodology to concentrate both loaded and unloaded liposomes without affecting the quality of the processed product.

A comparison among ß-caseins purified from milk of different species: Self-assembling behaviour and immunogenicity potential.

Caseins are a family of proteins constituted by α-caseins (αs-1 and αs-2 caseins), ß-caseins and κ-caseins. ß-caseins, in particular, show a temperature and concentration-dependent self-assembling behaviour. Recently, ß-casein micelles have been proposed as natural nanocarriers for the delivery of hydrophobic compounds, promoting their bioavailability. Until now, all studies regarding both chemical-physical characterization and applications of ß-caseins have employed the protein of bovine origin. However, it could be interesting to exploit the use of ß-caseins from other milk sources for their potential encapsulation ability and immunogenicity but, at present, no information on the self-assembling behaviour is available for ß-caseins from the milk of species different from bovine. In this work, for the first time, ß-caseins from human milk and from donkey, goat, and sheep milk were purified and their self-assembling behaviour was compared to that of a commercial bovine ß-casein, the only one for which the concentration and temperature aggregation behaviour is known. Furthermore, a preliminary evaluation of the immunogenicity potential of ß-casein from other milk sources has been performed by cross-reaction experiments using anti-ß-casein antibodies from bovine origin. The results indicated a similar self-assembling profile among all ß-caseins examined compared to the bovine ß-casein, suggesting the possible use of ß-casein from other milk sources as nanocarriers. Since donkey and human ß-casein do not cross-react with bovine anti-ß-casein antibodies, they could be particularly interesting for the development of self-assembling systems with lower hypoallergenic potential.

Potentially Inappropriate Prescribing of Oral Solid Medications in Elderly Dysphagic Patients.

Pharmaceutical formulations suitable for dysphagic patients are not always commercially available, motivating caregivers to crush tablets or open capsules to facilitate swallowing. Since this action may modify the characteristics of the medicine, it should be considered potentially inappropriate. This paper is the first to focus on how hospitalization affected the rate of potentially inappropriate prescriptions (PIPs) and the incidence of dosage form-related PIPs in elderly patients with dysphagia. Data was collected by reviewing patient medical records in the Italian National Research Center on Aging of Ancona. The therapy at admission and discharge was analysed in terms of: inappropriate drug associations, inappropriate drugs for dysphagic patients, inappropriate dosage forms and inappropriate dosage form modifications. Forty-one dysphagic patients with an average age of 88.3 years were included in the study and 451 prescriptions were analysed. PIPs were widespread at admission, and hospitalization did not improve the situation in a statistically significant manner. The most common PIPs identified (>80%) were related to dosage form selection and modification. This study highlights a clear need for continuing medical education about prescription appropriateness and modification of solid dosage forms in patients with dysphagia.

A Tailored Thermosensitive PLGA-PEG-PLGA/Emulsomes Composite for Enhanced Oxcarbazepine Brain Delivery via the Nasal Route.

The use of nanocarrier delivery systems for direct nose to brain drug delivery shows promise for achieving increased brain drug levels as compared to simple solution systems. An example of such nanocarriers is emulsomes formed from lipid cores surrounded and stabilised by a corona of phospholipids (PC) and a coating of Tween 80, which combines the properties of both liposomes and emulsions. Oxcarbazepine (OX), an antiepileptic drug, was entrapped in emulsomes and then localized in a poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymer thermogel. The incorporation of OX emulsomes in thermogels retarded drug release and increased its residence time (MRT) in rats. The OX-emulsome and the OX-emulsome-thermogel formulations showed in vitro sustained drug release of 81.1 and 53.5%, respectively, over a period of 24 h. The pharmacokinetic studies in rats showed transport of OX to the systemic circulation after nasal administration with a higher uptake in the brain tissue in case of OX-emulsomes and highest MRT for OX-emulsomal-thermogels as compared to the IN OX-emulsomes, OX-solution and Trileptal® suspension. Histopathological examination of nasal tissues showed a mild vascular congestion and moderate inflammatory changes around congested vessels compared to saline control, but lower toxic effect than that reported in case of the drug solution.

Chitosan-based nanosystems and their exploited antimicrobial activity.

Chitosan is a biodegradable and biocompatible natural polysaccharide that has a wide range of applications in the field of pharmaceutics, biomedical, chemical, cosmetics, textile and food industry. One of the most interesting characteristics of chitosan is its antibacterial and antifungal activity, and together with its excellent safety profile in human, it has attracted considerable attention in various research disciplines. The antimicrobial activity of chitosan is dependent on a number of factors, including its molecular weight, degree of deacetylation, degree of substitution, physical form, as well as structural properties of the cell wall of the target microorganisms. While the sole use of chitosan may not be sufficient to produce an adequate antimicrobial effect to fulfil different purposes, the incorporation of this biopolymer with other active substances such as drugs, metals and natural compounds in nanosystems is a commonly employed strategy to enhance its antimicrobial potential. In this review, we aim to provide an overview on the different approaches that exploit the antimicrobial activity of chitosan-based nanosystems and their applications, and highlight the latest advances in this field.

Potassium canrenoate compounding for administration via enteral feeding tubes: a physical and microbiological stability study.

BACKGROUND: Swallowing difficulties are arising in an increasing number of patients, especially in elderly people. When deglutition ability is completely compromised, enteral administration of a drug via feeding tubes is used. Licensed pharmacists have to compound the original solid forms to enable this drug therapy. OBJECTIVES: To evaluate the possibility of compounding original commercial tablets to produce a liquid formulation suitable for administering via a feeding tube. METHODS: Two liquid formulations containing potassium canrenoate 5 mg/mL were prepared: a standard solution obtained by solubilising raw material and an extemporaneous preparation obtained by dissolving film-coated 100 mg tablets. Spectrophotometric determinations (UV range) of the drug established chemical stability of the analyte up to 60 days. Samples were tested for microbial growth. Gravimetric quantifications of liquid formulations were used to check any weight loss during the different steps before enteral administration. RESULTS: UV data confirmed the chemical stability of potassium canrenoate up to 60 days. Samples showed no microbial growth. A higher weight loss was recorded in extemporaneous preparations than in the standard solution (10.7% vs 7.6%) according to the gravimetric quantification. CONCLUSION: It is possible to compound the original tablets into a liquid formulation suitable for administration via a feeding tube.

Heating treatments affect the thermal behaviour of doxorubicin loaded in PEGylated liposomes.

Doxil® is a stealth marketed PEGylated liposomal formulation, containing the anticancer drug doxorubicin. After loading via a pH gradient, fibrillar supramolecular structures of doxorubicin sulfate originates inside the core of the liposomes. Recently, the crystallinity of doxorubicin sulfate has been confirmed by high-resolution calorimetry. However, no detailed information are available on the nature of doxorubicin sulfate nanocrystals and on the effect of different thermal treatments. Thus, the aim of this work was to characterize the thermal behaviour of Doxil® in comparison to the unloaded liposomes using microcalorimetry, dynamic light scattering and high-resolution ultrasound spectroscopy (HR-US). Different thermal programmes were applied with the aim to highlight the effect of the treatments on the formulation. The used techniques confirmed the ordered state of doxorubicin nanocrystals inside PEGylated liposomes. Particularly, microcalorimetry and HR-US highlighted the changes in the thermal behaviour of the drug under different heating programmes. Doxorubicin nanocrystals were found to be stable after heating up to 80°C, but an irreversible thermal behaviour was observed after a prolonged heating at elevated temperature (2h at 80°C). The non-reversibility could be related to the formation of a different ordered structure and enhanced by the slight leakage of the drug occurring after a prolonged heating.