Implications of crystal disorder on the solid-state stability of Olanzapine.

Mechanical perturbations of drug during solid pharmaceutical processing like milling can often generate crystal disorder posing serious implications to drug's stability. While physical changes like amorphization, recrystallization, polymorphism of the disordered drugs are extensively studied and reported in the literature, the propensities and inter-dependencies of recrystallization and degradation propensities of disordered drugs have seldom received deep attention. Previous investigations from our lab have explored some of these interplays, aiming to develop predictive stability models. As a follow-up, the implication of crystal disorder on the oxidative instability of Olanzapine (OLA) during accelerated storage is investigated in this work. Cryo-milling OLA at varied time intervals generated different extents of crystal disorder. The milled samples were characterized using calorimetry and infrared (IR) spectroscopy to examine the physical state, while their degradation was evaluated using ultra-performance liquid chromatographic methods. An X-ray amorphous OLA sample was generated by melt-cooling, and used as an amorphous reference. The crystallinity of the cryo-milled samples was quantified using a partial least square regression model based on ATR-FTIR spectroscopic data. The cryo-milled samples were exposed to different accelerated stability conditions along with crystalline (unmilled) and quench cooled (amorphous) samples, serving as controls. At periodic intervals, samples were removed from the stability storage, and analyzed using ATR-FTIR and UPLC methods to quantify the crystallinity- and degradation extents. A positive relation was witnessed between the initial degree of crystallinity and degradation kinetics of the disordered OLA samples during stability storage indicating a strong dependency of degradation on the disorder contents for such disordered solids. The results obtained in this study can potentially explain consequences of inter-batch variations of drugs during stability storage, in addition to enabling de-risking strategies towards eliminating solid drug instabilities in product development.

Evaluation of different techniques for wet granulation and pelletization processes using milk as innovative pharmaceutical excipient for pediatric use.

The present study focused on the use of milk as a novel excipient for the manufacture of pharmaceutical dosage forms specifically designed for the pediatric population. Dairy milks with different fat contents were studied to deliver paracetamol orally. The World Health Organization included milk in the list of GRAS (generally recognized as safe) substances, which together with its taste-masking ability and solubility solving properties, makes it a good candidate as an excipient in formulations containing paracetamol for pediatrics. The influence of the fat content in the milk, the fraction of paracetamol, the type of diluent and drying temperature (considered independent variables) were systematically investigated using a Design of Experiments (DoE) approach for the preparation of granules for oral administration, by wet agglomeration using different processing techniques, enabled the construction of mathematical models reflecting the correlation between the variables. Four different techniques were evaluated: wet granulation by low shear mixer, wet granulation by high shear mixer, wet granulation by fluidized bed, and extrusion and spheronization. The granules and pellets obtained were characterized for size, and size distribution of agglomerates, and complete release of the drug (dependent variables), according to the European Pharmacopoeia. The fraction of fat content in the milk promoted an increase on the dissolution rate of paracetamol. The key finding of the first two process techniques was a migration of paracetamol from powdered agglomerates towards the larger particles, probably due to friction and attrition events, which created a fraction of smaller size granules due to the fragmentation and loss of powder from the larger granules. The study has confirmed the potential of milk to be a novel and efficient excipient that can be used as a liquid binder in various agglomeration techniques to deliver drugs orally.

Effect of processing and formulation factors on Catalase activity in tablets.

The manufacturing of tablets containing biologics exposes the biologics to thermal and shear stresses, which are likely to induce structural changes (e.g., aggregation and denaturation), leading to the loss of their activity. Saccharides often act as stabilizers of proteins in formulations, yet their stabilizing ability throughout solid oral dosage processing, such as tableting, has been barely studied. This work aimed to investigate the effects of formulation and process (tableting and spray-drying) variables on catalase tablets containing dextran, mannitol, and trehalose as potential stabilizers. Non-spray-dried and spray-dried formulations were prepared and tableted (100, 200, and 400 MPa). The enzymatic activity, number of aggregates, reflecting protein aggregation and structure modifications were studied. A principal component analysis was performed to reveal underlying correlations. It was found that tableting and spray-drying had a notable negative effect on the activity and number of aggregates formed in catalase formulations. Overall, dextran and mannitol failed to preserve the catalase activity in any unit operation studied. On the other hand, trehalose was found to preserve the activity during spray-drying but not necessarily during tableting. The study demonstrated that formulation and process variables must be considered and optimized together to preserve the characteristics of catalase throughout processing.

Ethnomedicinal Usage, Phytochemistry and Pharmacological Potential of Solanum surattense Burm. f.

Solanum surattense Burm. f. is a significant member of the Solanaceae family, and the Solanum genus is renowned for its traditional medicinal uses and bioactive potential. This systematic review adheres to PRISMA methodology, analyzing scientific publications between 1753 and 2023 from B-on, Google Scholar, PubMed, Science Direct, and Web of Science, aiming to provide comprehensive and updated information on the distribution, ethnomedicinal uses, chemical constituents, and pharmacological activities of S. surattense, highlighting its potential as a source of herbal drugs. Ethnomedicinally, this species is important to treat skin diseases, piles complications, and toothache. The fruit was found to be the most used part of this plant (25%), together with the whole plant (22%) used to treat different ailments, and its decoction was found to be the most preferable mode of herbal drug preparation. A total of 338 metabolites of various chemical classes were isolated from S. surattense, including 137 (40.53%) terpenoids, 56 (16.56%) phenol derivatives, and 52 (15.38%) lipids. Mixtures of different parts of this plant in water-ethanol have shown in vitro and/or in vivo antioxidant, anti-inflammatory, antimicrobial, anti-tumoral, hepatoprotective, and larvicidal activities. Among the metabolites, 51 were identified and biologically tested, presenting antioxidant, anti-inflammatory, and antitumoral as the most reported activities. Clinical trials in humans made with the whole plant extract showed its efficacy as an anti-asthmatic agent. Mostly steroidal alkaloids and triterpenoids, such as solamargine, solanidine, solasodine, solasonine, tomatidine, xanthosaponin A-B, dioscin, lupeol, and stigmasterol are biologically the most active metabolites with high potency that reflects the new and high potential of this species as a novel source of herbal medicines. More experimental studies and a deeper understanding of this plant must be conducted to ensure its use as a source of raw materials for pharmaceutical use.

Exploring Environmental Settings to Improve the Printability of Paroxetine-Loaded Filaments by Fused Deposition Modelling.

The successful integration of hot-melt extrusion (HME) and fused deposition modelling (FDM) depends on a better understanding of the impact of environmental conditions on the printability of formulations, since they significantly affect the properties of the raw materials, whose control is crucial to enable three-dimensional printing (3DP). Hence, the objective of this work was to investigate the correlation between the environmental settings and the properties of paroxetine (PRX)-loaded filaments, previously produced by HME, which affect printability by FDM. The influence of different drying methods of the physical mixtures (PMs) and HME-filaments (FILs) on the quality and printability of these products was also assessed. The printability of FILs was evaluated in terms of the water content, and the mechanical and thermal properties of the products. Stability studies and physicochemical, thermal, and in vitro dissolution tests were carried out on the 3D-printed tablets. Stability studies demonstrated the high ductility of the PRX loaded FILs, especially under high humidity conditions. Under low humidity storage conditions (11% RH), the FILs became stiffer and were successfully used to feed the FDM printer. Water removal was slow when carried out passively in a controlled atmosphere (desiccator) or accelerated by using active drying methods (heat or microwave). Pre-drying of the PRX/excipients and/or PMs did not show any positive effect on the printability of the FIL. On the contrary, dry heat and, preferably, microwave mediated drying processes were shown to reduce the holding time required for successful FDM printing, enabling on-demand production at the point of care.

The Genus Diospyros: A Review of Novel Insights into the Biological Activity and Species of Mozambican Flora.

Species of the Diospyros L. genus (Ebenaceae family) have been largely used in traditional medicine for the treatment of several diseases, especially infectious ones. To date, active major compounds such as naphthoquinones, triterpenoids, and tannins have been isolated and pharmacologically validated from Diospyros species. The present study summarizes the information available in the literature on the species described in the Flora of Mozambique. To do so, scientific databases (e.g., PubMed, Scopus, Web of Science, and Google Scholar) were searched using various keywords and Boolean connectors to gather and summarize the information. Of the 31 native and naturalized species in the Flora of Mozambique, 17 are used in different regions of Africa and were described for their traditional uses. They were reported to treat more than 20 diseases, mostly infectious, in the gastrointestinal and oral cavity compartments. This work provides an overview of the therapeutical potential of Diospyros species and explores novel insights on the antimicrobial potential of extracts and/or isolated compounds of these Mozambican species.

In vitro dissolution/permeation tools for amorphous solid dispersions bioavailability forecasting I: Experimental design for PermeaLoop™.

Along with the increasing demand for candidate-enabling formulations comes the need for appropriate in vitro bioavailability forecasting. Dissolution/permeation (D/P) systems employing cell-free permeation barriers are increasingly gaining interest, due to their low cost and easy application as passive diffusion bio-predictive profiling in drug product development, as this accounts for nearly 75% of new chemical entities (NCEs) absorption mechanism. To this end, this study comprises theoretical considerations on the design and experimental work towards the establishment and optimization of a PermeaLoop™ based dissolution/permeation assay to simultaneously evaluate the drug release and permeation using Itraconazole (ITZ)-based amorphous solid dispersions (ASD) formulations, with different drug loads, based on a solvent-shift approach. Alternative method conditions were tested such as: donor medium, acceptor medium and permeation barrier were screened using both PermeaPad® and PermeaPlain® 96-well plates. A range of solubilizers, namely Sodium Dodecyl Sulfate, Vitamin E-TPGS and hydroxypropyl-ß-cyclodextrin, were screened as possible solubilizing additives to the acceptor medium, while donor medium was varied between blank FaSSIF (phosphate buffer) and FaSSIF. The method optimization also included the ITZ dose selection, being the ITZ single dose (100 mg) considered the most adequate to be used in further experiments to allow the comparison with in vivo studies. In the end, a standardized approach that may be applied to predict the bioavailability of weakly basic poorly soluble drug-based formulations is described, contributing to strengthening the analytical portfolio of in vitro pre-clinical drug product development.

In vitro dissolution/permeation tools for amorphous solid dispersions bioavailability forecasting II: Comparison and mechanistic insights.

Along with the increasing demand for complex formulations comes the need for appropriate in vitro methodologies capable of predicting their corresponding in vivo performance and the mechanisms controlling the drug release which can impact on in vivo drug absorption. In vitro dissolution-permeation (D/P) methodologies that can account for the effects of enabling formulations on the permeability of drugs are increasingly being used in performance ranking during early development stages. This work comprised the application of two different cell-free in vitro D/P setups: BioFLUX™ and PermeaLoop™ to evaluate the dissolution-permeation interplay upon drug release from itraconazole (ITZ)- HPMCAS amorphous solid dispersions (ASDs) of different drug loads. A solvent-shift approach was employed, from a simulated gastric environment to a simulated intestinal environment in the donor compartment. PermeaLoop™ was then combined with microdialysis sampling to separate the dissolved (free) drug from other species present in solution, like micelle-bound drug and drug-rich colloids, in real time. This setup was applied to clarify the mechanisms for drug release and permeation from these ASDs. In parallel, a pharmacokinetic study (dog model) was conducted to assess the drug absorption from these ASDs and to compare the in vivo results with the data obtained from each in vitro D/P setup, allowing to infer which would be the most adequate setup for ASD ranking. Even though both D/P systems resulted in the same qualitative ranking, BioFLUX™ overpredicted the difference between the in vivo AUC of two ASDs, whereas PermeaLoop™ permeation flux resulted in a good correlation with the AUC observed in pharmacokinetic studies (dog model) (R2 ≈ 0.98). Also, PermeaLoop™ combined with a microdialysis sampling probe clarified the mechanisms for drug release and permeation from these ASDs. It demonstrated that the free drug was the only driving force for permeation, while the drug-rich colloids kept permeation active for longer periods by acting as drug reservoirs and maintaining constant high levels of free drug in solution, which are then immediately able to permeate. Hence, the data obtained points BioFLUX™ and PermeaLoop™ applications to different momentums in the drug product development pipeline: while BioFLUX™, an automated standardized method, poses as a valuable tool for initial ASD ranking during the early development stages, PermeaLoop™ combined with microdialysis sampling allows to gain mechanistic understanding of the dissolution-permeation interplay, being crucial to fine tune and identify leading ASD candidates prior to in vivo testing.

Development of fast dissolving polymer-based microneedles for delivery of an antigenic melanoma cell membrane.

Delivery of cancer cell membranes (CM) is a new approach for the activation of the immune system and the induction of immunotherapy of cancer. Local delivery of melanoma CM into skin can induce efficient immune stimulation of antigen presenting cells (APCs), such as dendritic cells. In the current study, fast dissolving microneedles (MNs) were developed for the delivery of melanoma B16F10 CM. Two polymers were tested for the fabrication of MNs: poly(methyl vinyl ether-co-maleic acid) (PMVE-MA) and hyaluronic acid (HA). The incorporation of CM in MNs was achieved through coating of the MNs using a multi-step layering procedure or the micromolding technique. The CM loading and its stabilization were improved by adding sugars (sucrose and trehalose) and a surfactant (Poloxamer 188), respectively. In an ex vivo experiment, both PMVE-MA and HA showed fast dissolutions (<30 s) after insertion into porcine skin. However, HA-MN showed better mechanical properties, namely improved resistance to fracture when submitted to a compression force. Overall, a B16F10 melanoma CM-dissolving MN system was efficiently developed as a promising device suggesting further studies in immunotherapy and melanoma applications.

Comprehensive powder flow characterization with reduced testing.

Powder flow is a critical attribute of pharmaceutical blends to ensure tablet weight uniformity and production of tablets with consistent and reproducible properties. This study aims at characterizing different powder blends with a number of different rheologic techniques, in order to understand how particles' attributes and interaction between components within the formulation generate different responses when analysed by different rheological tests. Furthermore, this study intends on reducing the number of tests in early development phases, by selecting the ones that provide the best information about the flowability attributes of the pharmaceutical blends. This work considered two cohesive powders - spray-dried hydroxypropyl cellulose (SD HPMC) and micronized indomethacin (IND) - formulated with other four commonly used excipients [(lactose monohydrated (LAC), microcrystalline cellulose (MCC), magnesium stearate (MgSt) and colloidal silica (CS)]. The experimental results showed that powder flowability may be affected by materials particles' size, bulk density, morphology, and interactions with lubricant. In detail, parameters, such as angle of repose (AoR), compressibility percentage (CPS), and flow function coefficient (ffc) have shown to be highly affected by the particle size of the materials present in the blends. On the other hand, the Specific Energy (SE) and the effective angle of internal friction (φe) showed to be more related with particle morphology and materials interaction with the lubricant. Since both ffc and φe parameters are generated from the yield locus test, data suggest that a number of different powder flow features may be understood only by applying this test, avoiding redundant powder flow characterization, as well as extensive time and material spent in early development formulation stages.

Influence of formulation variables on the processability and properties of tablets manufactured by fused deposition modelling.

The present work studied the influence of different formulation variables (defined also as factors), namely, different polymers (HPC EF, PVA and HPMC-AS LG), drugs with different water solubilities (paracetamol, hydrochlorothiazide and celecoxib) and drug loads (10 or 30 %) on their processability by HME and FDM. Both filaments and tablets were characterized for physic and chemical properties (DSC, XRPD, FTIR) and performance properties (drug content, in vitro drug release). Experiments were designed to highlight relationships between the 3 factors selected and the mechanical properties of filaments, tablet mass and dissolution profiles of the model drugs from printed tablets. While the combination of hydrochlorothiazide and HPMC-AS LG could not be extruded, the combination of paracetamol with HPC EF turned the filaments too ductile and not stiff enough hampering the process of printing. All other polymer and drug combinations could be successfully extruded and printed. Models reflected the influence of the solubility of the drug considered but not the drug load in formulations. The ranking of the drug release rates was in good agreement with their solubilities. Furthermore, PVA presenting the fastest swelling rate, promoted the fastest drugs' releases in comparison with the other polymers studied. Overall, the study enabled the identification of the key factors affecting the properties of printed tablets, with the proposal of a model that has valued the relative contribution of each factor to the overall performance of tablets.

Production of Bi-Compartmental Tablets by FDM 3D Printing for the Withdrawal of Diazepam.

Diazepam (DZP) is a long-acting benzodiazepine to treat anxiety or acute alcohol withdrawal. Although this class of drugs should be taken for a short period of time, many patients take them for longer than recommended, which has been linked to an increased risk of dementia and dependence. The present work aimed at using the dual-nozzle system of fused deposition modeling (FDM) 3D printers to prepare tablets with gradual doses of DZP with constant mass and size. Placebo and DZP-loaded filaments were prepared by hot-melt extrusion and used to print the bi-compartmental tablets. Thermal processing allowed the conversion of crystalline DZP to its amorphous counterpart. Tablets with different DZP contents were effectively printed with a mass, thickness and diameter average of 111.6 mg, 3.1 mm, and 6.4 mm, respectively. Microscopic data showed good adhesion between the different layers in the printed tablets. The desired drug contents were successfully achieved and were within the acceptance criteria (European Pharmacopeia). The combination of a placebo and drug-loaded extrudates proved to be beneficial in the production of tablets by FDM for patients in need of drug withdrawal.

Mechanoactivation as a Tool to Assess the Autoxidation Propensity of Amorphous Drugs.

Mechanoactivation has attracted considerable attention in the pharmaceutical sciences due to its ability to generate amorphous materials and solid-state synthetic products without the use of solvent. Although some studies have reported drug degradation during milling, no studies have systematically investigated the use of mechanoactivation in predicting drug degradation in the solid state. Thus, this work explores the autoxidation of drugs in the solid state by comilling amorphous mifepristone (MFP):polyvinylpyrrolidone vinyl acetate (PVPVA) and amorphous olanzapine (OLA):PVPVA. MFP was amorphized by ball milling and OLA by quench cooling techniques. Subsequently, comilling the amorphous drugs in the presence of a 10-fold weight ratio of PVPVA (the excipient containing reactive free radicals) was performed at several milling frequencies to identify the kinetics of mechano-autoxidation over milling durations. Overall, milling led to the degradation of up to 5% drug in the solid state. The autoxidation mechanism was confirmed by performing a stress study in the solution at 50 °C for 5 h, by using a 10 mM azo-bis(isobutyronitrile) (AIBN) as a stressing agent. By deconvoluting the effect of milling frequency and the energy on the extent and kinetics of milling-induced autoxidation of amorphous drugs, it was possible to fit an extended Arrhenius model that allowed extrapolation of mechanoactivated degradation rates (Km) to zero milling frequencies. Further, the autoxidation rates of drugs stored at high temperatures were observed to follow an Arrhenius behavior. A good degree of agreement was observed between the model predictions obtained by mechanoactivation (Km) to the reaction rates observed under accelerated temperatures. Additionally, the impact of adding an antioxidant (e.g., butylated hydroxytoluene) to the mixture during comilling was also examined. This study can be helpful in evaluating the stability of amorphous solids stored in accelerated (non-hermetic) conditions, in screening solid-state autoxidation propensity of drugs, and for the rational selection of antioxidants.

Microfluidic preparation and optimization of sorafenib-loaded poly(ethylene glycol-block-caprolactone) nanoparticles for cancer therapy applications.

The use of amphiphilic block copolymers to generate colloidal delivery systems for hydrophobic drugs has been the subject of extensive research, with several formulations reaching the clinical development stages. However, to generate particles of uniform size and morphology, with high encapsulation efficiency, yield and batch-to-batch reproducibility remains a challenge, and various microfluidic technologies have been explored to tackle these issues. Herein, we report the development and optimization of poly(ethylene glycol)-block-(ε-caprolactone) (PEG-b-PCL) nanoparticles for intravenous delivery of a model drug, sorafenib. We developed and optimized a glass capillary microfluidic nanoprecipitation process and studied systematically the effects of formulation and process parameters, including different purification techniques, on product quality and batch-to-batch variation. The optimized formulation delivered particles with a spherical morphology, small particle size (dH < 80 nm), uniform size distribution (PDI < 0.2), and high drug loading degree (16 %) at 54 % encapsulation efficiency. Furthermore, the stability and in vitro drug release were evaluated, showing that sorafenib was released from the NPs in a sustained manner over several days. Overall, the study demonstrates a microfluidic approach to produce sorafenib-loaded PEG-b-PCL NPs and provides important insight into the effects of nanoprecipitation parameters and downstream processing on product quality.

In Situ Co-Amorphization of Olanzapine in the Matrix and on the Coat of Pellets.

In situ amorphization is a promising approach, considered in the present work, to enhance the solubility and dissolution rate of olanzapine, while minimizing the exposure of the amorphous material to the stress conditions applied during conventional processing. The production of pellets by extrusion/spheronization and the coating of inert beads were investigated as novel methods to promote the co-amorphization of olanzapine, a poorly water-soluble drug, and saccharin. Samples were characterized using differential scanning calorimetry, X-ray powder diffraction, Fourier-transform infrared spectroscopy and scanning electron microscopy, and dissolution and stability testing. The co-amorphous produced were compared with crystalline olanzapine, or physical mixture of olanzapine and saccharin. Results suggested that the addition of water to mixtures containing olanzapine and saccharin during the production of pellets, and the coating of inert beads, induced the in situ co-amorphization of these substances. The coating of inert beads enhanced the solubility and dissolution rate of olanzapine, especially when compared to pellets coated with the crystalline drug, but also with pellets containing the co-amorphous entity in the matrix of beads. Nine months stability tests (23 °C/60% RH) confirmed the preservation of the solid-state properties of the co-amorphous form on/in pellets. Overall, results highlighted the feasibility and benefits of in situ co-amorphization, either when the drug was entrapped in the pellets matrix, or preferentially applied directly on the surface of pellets.

Diospyros villosa Root Monographic Quality Studies.

Diospyros villosa L. (De Winter) (Ebenaceae) is a shrub whose root (DVR) is used as a toothbrush and to treat oral infections in Mozambique. The present work aims at establishing monographic quality criteria to allow the sustainable and safe development of pharmaceutical preparations with this herbal drug. This includes setting botanical (qualitative and quantitative) and chemical identification parameters, purity tests (loss on drying and total ash), quantifying the major classes of constituents identified, and particle size characterization of the powdered drug. DVR samples are cylindrical and microscopically characterized by: a periderm, with six layers of flattened phellem cells, with slightly thickened walls and few layers of phelloderm; cortical parenchyma with brachysclereids with a short, roughly isodiametric form (13.82-442.14 µm2 × 103), surrounded by a ring of prismatic calcium oxalate crystals; uniseriate medullary rays and prominent vessels of the xylem with single or double shape; numerous single and clustered starch grains, within the cortical parenchyma, medullar parenchyma, and ray cells. Polyphenols, mainly hydrolyzable tannins (212.29 ± 0.005 mg gallic acid equivalent/g of dried DVR), are the main marker class of constituents. Furthermore, the average diameter of the particles of the powder, 0.255 mm, allows its classification as a fine powder.

Amorphous and Co-Amorphous Olanzapine Stability in Formulations Intended for Wet Granulation and Pelletization.

The preparation of amorphous and co-amorphous systems (CAMs) effectively addresses the solubility and bioavailability issues of poorly water-soluble chemical entities. However, stress conditions imposed during common pharmaceutical processing (e.g., tableting) may cause the recrystallization of the systems, warranting close stability monitoring throughout production. This work aimed at assessing the water and heat stability of amorphous olanzapine (OLZ) and OLZ-CAMs when subject to wet granulation and pelletization. Starting materials and products were characterized using calorimetry, diffractometry and spectroscopy, and their performance behavior was evaluated by dissolution testing. The results indicated that amorphous OLZ was reconverted back to a crystalline state after exposure to water and heat; conversely, OLZ-CAMs stabilized with saccharin (SAC), a sulfonic acid, did not show any significant loss of the amorphous content, confirming the higher stability of OLZ in the CAM. Besides resistance under the processing conditions of the dosage forms considered, OLZ-CAMs presented a higher solubility and dissolution rate than the respective crystalline counterpart. Furthermore, in situ co-amorphization of OLZ and SAC during granule production with high fractions of water unveils the possibility of reducing production steps and associated costs.

Sulfonic Acid Derivatives in the Production of Stable Co-Amorphous Systems for Solubility Enhancement.

Co-amorphization is a promising approach to stabilize drugs in the amorphous form. Olanzapine, a poorly water-soluble drug was used in this study. Sulfonic acids (saccharin, cyclamic acid and acesulfame), free and in salt forms, were used as co-formers and compared with carboxylic acids commonly used in the preparation of co-amorphous systems. Several manufacturing techniques were tested, and the co-amorphous systems characterized by differential scanning calorimetry, X-ray powder diffraction, thermogravimetry and Fourier-transform infrared spectroscopy. Free sulfonic acids produced co-amorphous systems with the drug, unlike their salts. Spectroscopy data suggests the formation of salts between olanzapine and the sulfonic acids, used as co-formers. The co-amorphous system produced with saccharin by solvent evaporation, showed the most notable solubility enhancement (145 times). The stability of amorphous and co-amorphous olanzapine systems was assessed upon exposure to stress conditions during storage. Amorphized olanzapine readily reconverted back to the crystalline form while sulfonic acids:olanzapine co-amorphous were stable for up to 24 weeks in low/medium humidity conditions (11-75% RH). Results highlight the potential advantages offered by sulfonic acids as co-formers to produce stable and more soluble co-amorphous olanzapine.

Downstream Processing of Amorphous and Co-Amorphous Olanzapine Powder Blends.

The work evaluates the stability of amorphous and co-amorphous olanzapine (OLZ) in tablets manufactured by direct compression. The flowability and the compressibility of amorphous and co-amorphous OLZ with saccharin (SAC) and the properties of the tablets obtained were measured and compared to those of tablets made with crystalline OLZ. The flowability of the amorphous and mostly of the co-amorphous OLZ powders decreased in comparison with the crystalline OLZ due to the higher cohesiveness of the former materials. The stability of the amorphous and co-amorphous OLZ prior to and after tableting was monitored by XRPD, FTIR, and NIR spectroscopies. Tablets presented long-lasting amorphous OLZ with enhanced water solubility, but the release rate of the drug decreased in comparison with tablets containing crystalline OLZ. In physical mixtures made of crystalline OLZ and SAC, an extent of amorphization of approximately 20% was accomplished through the application of compaction pressures and dwell times of 155 MPa and 5 min, respectively. The work highlighted the stability of amorphous and co-amorphous OLZ during tableting and the positive effect of compaction pressure on the formation of co-amorphous OLZ, providing an expedited amorphization technique, given that the process development-associated hurdles were overcome.

The Precision and Accuracy of 3D Printing of Tablets by Fused Deposition Modelling.

Tablet manufacture by fused deposition modelling (FDM) can be carried out individually (one tablet printed per run) or as a group (i.e., 'multiple printing' in one run) depending on patient's needs. The assessment of the process of printing must take into consideration the precision and the accuracy of the mass and dose of tablets, together with their solid-state properties and drug dissolution behaviour. Different mixtures made of either poly(vinyl alcohol) and paracetamol or hydroxypropylcellulose EF and hydrochlorothiazide were used to evaluate multiple printing of tablets by manufacturing batches of 30 tablets with nozzles of 0.4 and 0.7 mm, in two different printers. Besides testing for mass, drug content, density and dissolution performance, tablets were analysed for their thermal (DSC) and spectroscopic (NIR and FTIR) properties. Low standard deviations around mean values for the different properties measured suggested low intra-batch variability. Statistical analysis of data revealed no significant differences between the batches for most of the properties considered in the study. Inter-batch differences (p<0.05) were observed only for mass of tablets, possibly due to deviation on filament's diameter. The use of a smaller nozzle or a different printer enabled the manufacture of more reproducible tablets within a batch. Multiple printing revealed a significant saving on manufacturing time (>35%) in comparison to individual printing.