Evaluation of Suitable Polymeric Matrix/Carriers during Loading of Poorly Water Soluble Drugs onto Mesoporous Silica: Physical Stability and In Vitro Supersaturation.

The application of mesoporous carriers in formulations of amorphous solid dispersions (ASDs) has been suggested to enhance the stability of amorphous drugs. However, mesoporous carriers do not demonstrate satisfactory inhibitory effects on the precipitation of active pharmaceutical ingredients (APIs), and the inclusion of an appropriate polymer within ASDs becomes imperative to maintaining drug supersaturation. The aim of this study was to evaluate ternary olanzapine (OLN) ASDs with Syloid 244FP and to find an appropriate polymeric carrier. The polymer's selection criteria were based on the physical stability of the ASDs and the release rate of the drug from the systems. The polymers investigated were hydroxypropylmethyl cellulose (HPMC) and copovidone (coPVP). The formation of ASDs was achievable in all investigated cases, as demonstrated by the complete lack of crystallinity confirmed through both powder X-ray diffraction (pXRD) analysis and differential scanning calorimetry (DSC) for all developed formulations. The solvent shift method was employed to evaluate the ability of the studied carriers to inhibit the precipitation of supersaturated OLN. coPVP emerged as a more suitable precipitation inhibitor compared with HPMC and Syloid 244 FP. Subsequently, in vitro dissolution studies under non-sink conditions revealed a higher degree of supersaturation in ternary systems where coPVP was used as a polymeric carrier, as these systems exhibited, under the examined conditions, up to a 2-fold increase in the released OLN compared with the pure crystalline drug. Moreover, stability studies conducted utilizing pXRD demonstrated that ternary formulations incorporating coPVP and Syloid 244 FP maintained stability for an extended period of 8 months. In contrast, binary systems exhibited a comparatively shorter stability duration, indicating the synergistic effect of coPVP and Syloid 244 FP on the physical stability of the amorphous API. Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) studies showed that the development of stronger molecular interactions can be provided as an explanation for this synergistic effect, as the formation of robust H-bonds may be considered responsible for inhibiting the precipitation of the supersaturated API. Therefore, the incorporation of coPVP into OLN ASDs with Syloid 244 FP is considered a highly promising technique for increasing the degree of OLN supersaturation in in vitro dissolution studies and improving the stability of systems.

The Role of Cone Beam Computed Tomography in Periodontology: From 3D Models of Periodontal Defects to 3D-Printed Scaffolds.

The treatment of osseous defects around teeth is a fundamental concern within the field of periodontology. Over the years, the method of grafting has been employed to treat bone defects, underscoring the necessity for custom-designed scaffolds that precisely match the anatomical intricacies of the bone cavity to be filled, preventing the formation of gaps that could allow the regeneration of soft tissues. In order to create such a patient-specific scaffold (bone graft), it is imperative to have a highly detailed 3D representation of the bone defect, so that the resulting scaffold aligns with the ideal anatomical characteristics of the bone defect. In this context, this article implements a workflow for designing 3D models out of patient-specific tissue defects, fabricated as scaffolds with 3D-printing technology and bioabsorbable materials, for the personalized treatment of periodontitis. The workflow is based on 3D modeling of the hard tissues around the periodontal defect (alveolar bone and teeth), scanned from patients with periodontitis. Specifically, cone beam computed tomography (CBCT) data were acquired from patients and were used for the reconstruction of the 3D model of the periodontal defect. The final step encompasses the 3D printing of these scaffolds, employing Fused Deposition Modeling (FDM) technology and 3D-bioprinting, with the aim of verifying the design accuracy of the developed methodοlogy. Unlike most existing 3D-printed scaffolds reported in the literature, which are either pre-designed or have a standard structure, this method leads to the creation of highly detailed patient-specific grafts. Greater accuracy and resolution in the macroarchitecture of the scaffolds were achieved during FDM printing compared to bioprinting, with the standard FDM printing profile identified as more suitable in terms of both time and precision. It is easy to follow and has been successfully employed to create 3D models of periodontal defects and 3D-printed scaffolds for three cases of patients, proving its applicability and efficiency in designing and fabricating personalized 3D-printed bone grafts using CBCT data.

Utilizing Drug Amorphous Solid Dispersions for the Preparation of Dronedarone per os Formulations.

Dronedarone (DRN), an antiarrhythmic drug, exhibits potent pharmacological effects in the management of cardiac arrhythmias. Despite its therapeutic potential, DRN faces formulation challenges due to its low aqueous solubility. Hence, the present study is dedicated to the examination of amorphous solid dispersions (ASDs) as a strategic approach for enhancing the solubility of DRN. Initially, the glass forming ability (GFA) of API was assessed alongside its thermal degradation profile, and it was revealed that DRN is a stable glass former (GFA III compound) that remains thermally stable up to approximately 200 °C. Subsequently, five commonly used ASD matrix/carriers, i.e., hydroxypropyl methylcellulose (HPMC), povidone (PVP), copovidone (PVP/VA), Soluplus® (SOL), and Eudragit® E PO (EPO), were screened for the formation of a DRN-based ASD using film casting and solvent shift methods, along with miscibility evaluation measurements. SOL proved to be the most promising matrix/carrier among the others, and, hence, was used to prepare DRN ASDs via the melt-quench method. The physicochemical characterization of the prepared systems (via pXRD) revealed the complete amorphization of the API within the matrix/carrier, while the system was physically stable for at least three months after its preparation. In vitro release studies for the ASDs, conducted under non-sink conditions, revealed the sustained supersaturation of the drug for at least 8 h. Finally, the use of attenuated total reflectance (ATR) FTIR spectroscopy showed the formation of a strong molecular interaction between the drug molecules and SOL.

A Review of the Role of Natural Products as Treatment Approaches for Xerostomia.

Xerostomia, commonly known as dry mouth, is a widespread oral health malfunction characterized by decreased salivary flow. This condition results in discomfort, impaired speech and mastication, dysphagia, heightened susceptibility to oral infections, and ultimately, a diminished oral health-related quality of life. The etiology of xerostomia is multifaceted, with primary causes encompassing the use of xerostomic medications, radiation therapy to the head and neck, and systemic diseases such as Sjögren's syndrome. Consequently, there is a growing interest in devising management strategies to address this oral health issue, which presents significant challenges due to the intricate nature of saliva. Historically, natural products have served medicinal purposes, and in contemporary pharmaceutical research and development, they continue to play a crucial role, including the treatment of xerostomia. In this context, the present review aims to provide an overview of the current state of knowledge regarding natural compounds and extracts for xerostomia treatment, paving the way for developing novel therapeutic strategies for this common oral health issue.

Assessing the performance of thermally crosslinked amorphous solid dispersions with high drug loadings.

Continuing what previous studies had also intended, the present study aims to shed light on some unanswered questions concerning a recently introduced class of high drug loading (HD) amorphous solid dispersions (ASDs), based on the in-situ thermal crosslinking of poly (acrylic acid) (PAA) and poly (vinyl alcohols) (PVA). Initially, the effect of supersaturated dissolution conditions on the kinetic solubility profiles of the crosslinked HD ASDSs having indomethacin (IND) as a model drug, was determined. Subsequently, the safety profile of these new crosslinked formulations was determined for the first time by evaluating their cytotoxic effect on human intestinal epithelia cell line (Caco-2), while their ex-vivo intestinal permeability was also studied via the non-everted gut sac method. According to the obtained findings, the in-situ thermal crosslinked IND HD ASDs present similar kinetic solubility profiles when the dissolution studies are conducted with a steady sink index value, regardless of the different dissolution medium's volume and the total dose of the API. Additionally, the results showed a concentration- and time- dependent cytotoxicity profile for all formulations, while the neat crosslinked PAA/PVA matrices did not elicit cytotoxicity during the first 24 h, even at the highest examined concentration. Finally, the newly proposed HD ASD system, resulted in a remarkably increased ex-vivo intestinal permeability of IND.

Preparation and Evaluation of Siderol Amorphous Solid Dispersions: Selection of Suitable Matrix/Carrier.

The present study investigates the preparation of amorphous solid dispersions (ASD) for the ent-kaurane diterpenoid siderol (SDR). Initially, evaluation of the pure drug (isolated from Sideritis scardica) revealed that the API is a non-stable glass former, and hence the selection of a suitable ASD's matrix/carrier needs special attention. For this reason, four commonly used polymers and copolymers, namely poly(vinylpyrrolidone), copovidone, hydroxypropyl cellulose, and Soluplus® (SOL), were screened via film casting and crystal growth rate measurements. Amongst them, SOL showed the highest SDR's crystal growth rate reduction, and, since it was also miscible with the drug, it was selected for further testing. In this direction, SDR-SOL ASDs were successfully prepared via melt-quench cooling. These formulations showed full API amorphization, while good physical stability (i.e., a stable SDR amorphous dispersions) were obtained after storage for several months. Finally, evaluation of molecular interactions (with the aid of ATR-FTIR spectroscopy) showed strong H-bonds between SOL and SDR, while the use of molecular dynamics (MD) simulations unraveled the nature of these interactions. Therefore, based on the findings of the present work, SOL seems to be an appropriate matrix/carrier for the preparation of SDR ASDs, although further studies are needed in order to explore its full potentials.

A Review on the Role of Pilocarpine on the Management of Xerostomia and the Importance of the Topical Administration Systems Development.

Xerostomia is linked to an increased risk of dental caries, oral fungal infections, and speaking/swallowing difficulties, factors that may significantly degrade patients' life, socially- or emotionally-wise. Consequently, there is an increasing interest in developing management approaches for confronting this oral condition, at which pilocarpine, a parasympathomimetic agent, plays a vital role. Although the therapeutic effects of orally administrated pilocarpine on the salivary gland flow and the symptoms of xerostomia have been proved by numerous studies, the systemic administration of this drug is affiliated with various adverse effects. Some of the typical adverse effects include sweating, nausea, vomiting, diarrhea, rhinitis, dizziness and increased urinary frequency. In this vein, new strategies to develop novel and effective dosage forms for topical (i.e., in the oral cavity) pilocarpine administration, in order for the salivary flow to be enhanced with minimal systemic manifestations, have emerged. Therefore, the purpose of the current review is to survey the literature concerning the performance of topical pilocarpine delivery systems. According to the findings, the topical delivery of pilocarpine can be regarded as the equivalent to systemic delivery of the drug, efficacy-wise, but with improved patient tolerance and less adverse effects.

A Review on Xerostomia and Its Various Management Strategies: The Role of Advanced Polymeric Materials in the Treatment Approaches.

The medical term xerostomia refers to the subjective sensation of oral dryness. The etiology seems to be multifactorial with the most frequently reported causes being the use of xerostomic medications, neck and head radiation, and systematic diseases (such as Sjögren's syndrome). Xerostomia is associated with an increased incidence of dental caries, oral fungal infections, and difficulties in speaking and chewing/swallowing, which ultimately affect the oral health-related quality of life. The development of successful management schemes is regarded as a highly challenging project due to the complexity of saliva. This is why, in spite of the fact that there are therapeutic options aiming to improve salivary function, most management approaches are alleviation-oriented. In any case, polymers are an integral part of the various formulations used in every current treatment approach, especially in the saliva substitutes, due to their function as thickening and lubricating agents or, in the case of mucoadhesive polymers, their ability to prolong the treatment effect. In this context, the present review aims to scrutinize the literature and presents an overview of the role of various polymers (or copolymers) on either already commercially available formulations or novel drug delivery systems currently under research and development.

Preparation and Evaluation of Amorphous Solid Dispersions for Enhancing Luteolin's Solubility in Simulated Saliva.

Luteolin (LUT), a bioactive flavonoid, possesses various pharmacological properties, including antioxidant, antimicrobial, anti-allergic, cardio-protective, and anti-cancer activity. Among them, LUT's administration for the treatment of periodontal disease is very promising. However, its low water solubility magnifies the challenge of formulating LUT into an effective dosage form. In this vein, the aim of the present study examines the preparation of amorphous solid dispersions (ASD) for the solubility improvement of LUT in saliva. At first, the physicochemical properties of the active pharmaceutical ingredient (API) were studied before the selection of the most suitable ASD matrix/carrier. For this reason, six commonly used polymeric ASD matrix/carriers (namely, povidone, PVP; copovidone, coPVP; hydroxypropyl cellulose, HPC-SL; hydroxypropyl methyl cellulose acetate succinate, HPMC-AS; Eudragit® RS, Eud-RS; and Soluplus®, SOL) were screened via the film casting method, as to whether they could suspend the drug's recrystallization. The most promising matrix/carriers were then evaluated, based on their ability to inhibit LUT's precipitation after its solubilization, via the solvent shift method. Based on both screening methods, it was determined that PVP was the most promising matrix/carrier for the preparation of LUT's ASDs. Hence, in a further step, after the successful testing of components' miscibility, LUT-PVP ASDs were prepared via the solvent evaporation method. These systems (examined via powder X-ray diffractometry, pXRD) showed full API amorphization immediately after preparation and excellent physical stability (since they were stable after 3 months of storage). The study of LUT-PVP ASD's ATR-FTIR (Attenuated Total Reflectance-Fourier Transform Infrared) spectra demonstrated strong H-bonds between the molecules of the drug and the matrix/carrier, while molecular dynamics (MD) simulations were able to shed light on these drug-matrix/carrier interactions, at a molecular level. Finally, in vitro dissolution studies in simulated saliva proved that the prepared ASDs were able to significantly enhance LUT's dissolution profile. Hence, according to findings of the present work, the preparation of LUT-ASDs utilizing PVP as the polymeric matrix/carrier is regarded as a highly promising technique for the improvement of API's solubility in the oral cavity.

High-Drug-Loading Amorphous Solid Dispersions via In Situ Thermal Cross-Linking: Unraveling the Mechanisms of Stabilization.

This article takes a step forward in understanding the mechanisms involved during the preparation and performance of cross-linked high-drug-loading (HDL) amorphous solid dispersions (ASDs). Specifically, ASDs, having 90 wt % poorly water-soluble drug indomethacin (IND), were prepared via in situ thermal cross-linking of poly(acrylic acid) (PAA) and poly(vinyl alcohol) (PVA) and thoroughly evaluated in terms of physical stability and in vitro supersaturation. Results showed that HDL ASDs having excellent active pharmaceutical ingredient (API) amorphous stability and prolonged in vitro supersaturation were prepared by fine tuning the cross-linking procedure. Unraveling of the processes involved during ASD's formation shed light on the significant role of the cross-linking conditions (i.e., temperature and time), the physicochemical properties of the API, and the hydrolysis level of the cross-linker as key factors in modulating ASD's stability. In-depth analysis of the prepared systems revealed the (1) reduction of API's molecular motions within the cross-linked polymeric networks (through API's strong spatial confinement), (2) the structural changes in the prepared cross-linked matrices (induced by the high API drug loading), and (3) the tuning of the cross-linking density via utilization of low-hydrolyzed PVA as the major mechanisms responsible for ASD's exceptional performance. Complementary analysis by means of molecular dynamics simulations also highlighted the vital role of strong drug-polymer intermolecular interactions evolving among the ASD components. Overall, the impression of the complexity of in situ cross-linked ASDs has been reinforced with the excessive variation of parameters investigated in the current study, offering thus insights up to the submolecular level to lay the groundwork and foundations for the comprehensive assessment of a new emerging class of HDL amorphous API formulations.

Drug Amorphous Solid Dispersions Based on Poly(vinyl Alcohol): Evaluating the Effect of Poly(propylene Succinate) as Plasticizer.

Although significant actions have been taken towards the utilization of poly(vinyl alcohol) (PVA) in the preparation of drug amorphous solid dispersions (ASDs) using fusion-based techniques (such as melt-quench cooling and hot-melt extrusion), several drawbacks regarding its rather high melting temperature and its thermal degradation profile make the use of the polymer extremely challenging. This is especially important when the active pharmaceutical ingredient (API) has a lower melting temperature (than PVA) or when it is thermally labile. In this vein, a previous study showed that newly synthesized polyester-based plasticizers may improve the processability and the thermal properties of PVA. However, the effects of such polyester-based plasticizers on the drug's physicochemical and pharmaco-technical properties are yet unknown. Hence, the aim of the present study is to extend our previous findings and evaluate the use of poly(propylene succinate) (PPSu, i.e., the most promising plasticizer in regard to PVA) in the preparation of drug-loaded PVA-based ASDs. Dronedarone (DRN), a poorly water-soluble API, was selected as a model drug, and drug ASDs (using either neat PVA or PVA-PPSu) were prepared using the melt-mixing/quench cooling approach at low melting temperatures (i.e., 170 °C). DSC and pXRD analysis showed that a portion of the API remained crystalline in the ASDs prepared only with the use of neat PVA, while the samples having PPSu as a plasticizer were completely amorphous. Further evaluation with ATR-FTIR spectroscopy revealed the formation of significant intermolecular interactions between the API and the PVA-PPSu matrix, which could explain the system's physical stability during storage. Finally, dissolution studies, conducted under nonsink conditions, revealed that the use of PVA-PPSu is able to maintain DRN's sustained supersaturation for up to 8 h.

Drug crystal growth in ternary amorphous solid dispersions: Effect of surfactants and polymeric matrix-carriers.

The present study evaluates the crystal growth rate of amorphous drugs when dispersed in different ternary polymeric amorphous solid dispersions (ASDs) in the presence of surfactants. Specifically, ternary ASDs of aprepitant (APT, selected as a model drug) were prepared via melt-quench cooling by evaluating three commonly used ASDs matrix/carriers, namely hydroxypropyl cellulose (HPC), poly(vinylpyrrolidone) (PVP) and the copolymer Soluplus® (SOL), and two suitable surfactants, namely d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (P407). Results showed that all components were completely miscible (verified via hot stage polarized microscopy) and both surfactants were acting as plasticizers to the API. APT's crystal growth rate was increased in the presence of both P407 and TPGS, while PVP was identified as the matrix/carrier with the greatest impact API's crystal growth rate inhibition. Interestingly, TPGS presented a noticeable synergistic effect when combined with PVP resulting in a further reduction of APT's crystal growth rate. Furthermore, evaluation of APT's nucleation induction time in dissolution medium (PBS pH 6.8) revealed PVP as the most effective crystallization inhibitor, whereas the addition of TPGS showed to improve PVP's ability to inhibit APT's recrystallization. Finally, the formation of intermolecular interactions in the ternary APT-PVP-TPGS provided an explanation for the observed PVP-TPGS synergistic effects, with molecular dynamics simulations being able to unravel the type and extent of these interactions on a theoretical basis.

Leflunomide Sustained Skin Delivery Based on Sulfobetaine-Modified Chitosan Nanoparticles Embedded in Biodegradable Polyesters Films.

The aim of the present study was to prepare a leflunomide (LFD) sustained release transdermal delivery system for the treatment of psoriasis. In this context, LFD-loaded nanoparticles (NPs) based on either neat chitosan (CS) or CS modified with [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SDAEM, a sulfobetaine zwitterionic compound) were initially prepared via ionotropic gelation and characterized in terms of in vitro dissolution, physicochemical, and antibacterial properties. Results showed that the use of the SDAEM-modified CS resulted in the formation of LFD-loaded NPs with improved wetting and solubilization properties, better in vitro dissolution profile characteristics (i.e., higher dissolution rate and extent), and improved (enhanced) antibacterial properties. The resultant LFD-loaded NPs were then embedded in suitable thin-film skin patches, prepared via spin-coating, utilizing two different biodegradable polyesters, namely methoxy polyethylene glycol-b-poly(L-lactide) (mPEG-b-PLA, at a ratio of 25/75 mPEG to PLA) and poly(lactic-co-glycolic acid) (PLGA at a ratio of 75/25 DL-lactide/glycolide copolymer). Results showed the formation of polymeric thin-films with no agglomeration (or trapped air) and uniform structure in all cases, while the LFD-loaded NPs were successfully embedded in the polymeric matrix. Analysis of the obtained in vitro dissolution profiles revealed a sustained release profile of the drug for up to approximately twelve days, while between the two proposed systems, the use of CS-SDAEM NPs (independently of the polyester type) was the most promising formulation approach.

Low Molecular Weight Oligomers of Poly(alkylene succinate) Polyesters as Plasticizers in Poly(vinyl alcohol) Based Pharmaceutical Applications.

The plasticizing effect of three low molecular weight oligomers of aliphatic poly(alkylene succinate) polyesters, namely poly(butylene succinate) (PBSu), poly(ethylene succinate) (PESu), and poly(propylene succinate) (PPSu), on partially hydrolyzed poly(vinyl alcohol) (PVA) used in melt-based pharmaceutical applications, was evaluated for the first time. Initially, the three aliphatic polyesters were prepared by the melt polycondensation process and characterized by differential scanning calorimetry (DSC), 1H NMR, intrinsic viscosity, and size exclusion chromatography (SEC). Subsequently, their effect on the thermophysical and physicochemical properties of PVA was thoroughly evaluated. According to the obtained results, PVA was completely miscible with all three polyesters, while PESu induced PVA's thermal degradation, with the phenomenon starting from ~220 °C, in contrast to PBSu and PPSu, where a thermal profile similar to PVA was observed. Furthermore, molecular interactions between PVA and the prepared poly(alkylene succinate) polyesters were revealed by DSC, ATR-FTIR, and molecular dynamics simulations. Finally, melt flow index (MFI) measurements showed that, in contrast to PBSu, the use of PESu or PPSu significantly improved PVA's melt flow properties. Hence, according to findings of the present work, only the use of low molecular weight PPSu is suitable in order to reduce processing temperature of PVA and improve its melt flow properties (plasticizing ability) without affecting its thermal decomposition.

Evaluation of rivaroxaban amorphous solid dispersions physical stability via molecular mobility studies and molecular simulations.

The present study evaluates the effect of molecular mobility and molecular interactions in the physical stability of rivaroxaban (RIV) - soluplus® (SOL) amorphous solid dispersions (ASDs). Initially, the use of Adam-Gibbs approach revealed that RIV's molecular mobility (below its glass transition temperature) is significantly reduced in the presence of SOL, while the use of ATR-FTIR spectroscopy showed the formation of hydrogen bonds (HBs) between the two ASD components, indicating that these two mechanisms can be considered as responsible for system's physical stability. Contrary to previously published reports, the utilization of ATR-FTIR spectroscopy in the present study was able to clarify, for the first time, the type of intermolecular interactions formed within the examined ASD system, while the presence of a separate drug-rich amorphous phase (significantly increasing as the content of the drug increases) was also identified. Furthermore, in order to gain an insight into the intermolecular interactions responsible for drug's amorphous phase separation, molecular dynamics (MD) simulation models were utilized as realistic representations of the actual systems. Analysis of the obtained trajectories showed that the formation of strong intermolecular HBs between RIV's secondary amide proton and its three carbonyl oxygens (originating from the οxazolidone, oxomorpholin and carboxamide part of the drug molecule) as well as the significant reduction of the available HB acceptors in SOL due to copolymer's chain shrinkage, were responsible for the formation of a separate drug-rich amorphous phase within the ASD.

Determination of the physical state of a drug in amorphous solid dispersions using artificial neural networks and ATR-FTIR spectroscopy.

The objective of the present study was to evaluate the use of artificial neural networks (ANNs) in the development of a new chemometric model that will be able to simultaneously distinguish and quantify the percentage of the crystalline and the neat amorphous drug located within the drug-rich amorphous zones formed in an amorphous solid dispersion (ASD) system. Attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy was used, while Rivaroxaban (RIV, drug) and Soluplus® (SOL, matrix-carrier) were selected for the preparation of a suitable ASD model system. Adequate calibration and test sets were prepared by spiking different percentages of the crystalline and the amorphous drug in the ASDs (prepared by the melting - quench cooling approach), while a 24 full factorial experimental design was employed for the screening of ANN's structure and training parameters as well as spectra region selection and data preprocessing. Results showed increased prediction performance, measured based on the root mean squared error of prediction (RMSEp) for the test sample, for both the crystalline (RMSEp (crystal) = 0.86) and the amorphous (RMSEp (amorphous) = 2.14) drug. Comparison with traditional regression techniques, such as partial least square and principle component regressions, revealed the superiority of ANNs, indicating that in cases of high structural similarity between the investigated compounds (i.e., the crystalline and the amorphous forms of the same compound) the implementation of more powerful/sophisticated regression techniques, such as ANNs, is mandatory.

Experimental, Thermodynamic, and Molecular Modeling Evaluation of Amorphous Simvastatin-Poly(vinylpyrrolidone) Solid Dispersions.

A crucial step for the selection of proper amorphous solid dispersion (ASD) matrix carriers is the in-depth assessment of drug/polymer physicochemical properties. In this context, the present study extends the work of previously published attempts by evaluating the formation of simvastatin (SIM)-poly(vinylpyrrolidone) (PVP) ASDs with the aid of thermodynamic and molecular modeling. Specifically, the implementation of both Flory-Huggins lattice theory and molecular dynamics (MD) simulations was able to predict the miscibility between the two components (a finding that was experimentally verified via differential scanning calorimetry (DSC) and hot stage polarized microscopy), while a complete temperature-concentration phase-transition profile was constructed, leading to the identification of the thermodynamically metastable and unstable ASD zones. Furthermore, as in the case of previously published reports, the analysis of the ASDs via Fourier transform infrared spectroscopy did not clarify the type and extent of observed molecular interactions. Hence, in the present study, a computer-based MD simulation model was developed for the first time in order to gain an insight into the properties of the observed interactions. MD amorphous assemblies of SIM, PVP, and their mixtures were initially developed, and the calculated glass transition temperatures were in close agreement with experimentally obtained results, indicating that the developed models could be considered as realistic representations of the actual systems. Furthermore, molecular interactions evaluation via radial distribution function and radius of gyration analysis revealed that increasing SIM content results in a significant PVP chain shrinkage, which eventually leads to SIM-SIM amorphous intermolecular interactions, leading to the formation of amorphous drug zones. Finally, MD-based results were experimentally verified via DSC.

Quality Risk Management and Quality by Design for the Development of Diclofenac Sodium Intra-articular Gelatin Microspheres.

The aim of the present study was to evaluate the development of an intra-articular nonsteroidal anti-inflammatory drug gelatin microsphere formulation based on quality risk management and quality by design approaches. Specifically, after setting the quality target product profile and the critical quality attributes, risk assessment was performed by constructing Ishikawa fishbone diagrams based on preliminary hazard analysis. A Plackett-Burman screening experimental design was applied in order to identify the factors (previously classified by risk assessment analysis as having high risk of failure) having a statistically significant impact on the formation of gelatin microspheres. Particle size, polydispersity index, and drug loading were used as responses, while diclofenac sodium was selected as a model drug. All drug-loaded gelatin microspheres were prepared by emulsion-crosslinking process. Screening results showed that gelatin type, surfactant type and quantity, oil phase type, emulsification speed, and glutaraldehyde's concentration had a statistically significant impact on microsphere's final and intermediate critical quality attributes. A design space was then constructed based on central composite design overlaying contour plots, while verification experiments for the optimum suggested formulation (derived from a set control strategy) showed good agreement between the predicted and the experimentally observed results. In addition, the physicochemical characterization of the optimum formulation showed the formation of significant molecular interactions between the drug and the gelatin matrix, leading to the complete amorphization of diclofenac within the microsphere structure, while dissolution release experiments showed a biphasic release profile which extended the drug's release for up to 30 days, governed by a Fickian diffusion release mechanism.

Partially hydrolyzed polyvinyl alcohol for fusion-based pharmaceutical formulation processes: Evaluation of suitable plasticizers.

The present study evaluates the effect of several pharmaceutical plasticizers on the thermo-physical and physicochemical properties of partially hydrolyzed poly(vinyl alcohol) (PVA) used in fusion-based pharmaceutical formulation processes. Specifically, the effect of mannitol (MAN), sorbitol (SOR), sucrose (SUC), anhydrous citric acid (CA), triethyl citrate (TEC) and low-molecular weight polyethylene glycol (PEG400) on PVA's melting properties, physical state and thermal degradation was evaluated via differential scanning calorimetry (DSC), powder X-ray diffractometry (pXRD) and thermo-gravimetric analysis (TGA). Results showed that the use of MAN, SOR, SUC and PEG400 led to the reduction of PVA's melting onset temperature, while MAN, SUC, CA and SOR were amorphously dispersed within PVA's matrix, and the addition of SUC and CA resulted in significant reduction of PVA's crystallinity. TGA results showed the formation of thermally highly unstable PVA mixtures in the cases of CA and TEC (degradation started from ~150 °C and ~125 °C, respectively), while significant molecular interactions were identified by FTIR in the cases of PVA-MAN, PVA-SOR and PVA-SUC. Hot-stage polarized microscopy (HSM) revealed PVA's melt miscibility only with MAN and SOR, while melt flow index (MFI) measurements showed that the use of MAN, SOR and PEG400 resulted in a significant improvement of PVA's melt flow properties. Finally, MD simulations were in close agreement with the experimental observations, indicating that they can be considered as a promising tool for the theoretical modelling of such systems.

Gelatin nanoparticles for NSAID systemic administration: Quality by design and artificial neural networks implementation.

The present study evaluates the preparation of systemic administrated NSAID gelatin nanoparticles with the aid of quality by design and artificial neural networks (ANNs). Specifically, two different preparation techniques (i.e. nanoprecipitation and two-step desolvation) were implemented for the formulation of diclofenac sodium (DLC) gelatin nanoparticles (GNs). Preliminary screening experiments showed that in the case of nanoprecipitation the best compromise (in terms of achieving both small particle size and high encapsulation efficiency) was the use of poloxamer 407 (as stabilizer) and acetone (as non-solvent), while in the case of two-step desolvation significant effect had the use of acetone, gelatin type and bloom number (type B with bloom 150 was selected for further evaluation). Implementation of a central composite experimental design (CCD), showed that in the case of nanoprecipitation the optimum formulation can be achieved at high poloxamer, high gelatin and moderate to high glutaraldehyde (GTA used for crosslinking) concentrations, while in the case of two-step desolvation high gelatin and GTA concentrations are needed. Artificial neural networks (ANN) implementation showed significantly improved prediction ability compared to MLR, while verification experiments showed good agreement between the ANN predicted and the experimentally obtained results. SEM analysis of the optimum suggested formulations showed nanoparticles with smooth surface, while powder X-ray diffraction (XRD) analysis showed the formation of amorphously dispersed systems, and Fourier transform infrared spectroscopy (FTIR) revealed the presence of molecular interactions irrespectively of the preparation method followed. A slightly faster release profile was observed in the case of nanoprecipitation based GNs, while all formulations followed biphasic release profile.