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Telmisartan is used in the treatment of Hypertension (high blood pressure), prevention of heart attacks, strokes and heart failure. It is an angiotensin II type -1 receptor antagonist. Telmisartan belongs to class II under biopharmaceutical classification system. Hence, the solubility is the main issue. To increase the oral absorption, telmisartan requires enhancement in solubility and dissolution. The present study was aimed to increase the solubility of telmisartan by various techniques such as complexation and Solid dispersion. The tablet formulation was prepared to enhance the solubility and dissolution and compared with the drug release profile of the marketed preparation.

International audience; This study describes the preparation, characterization, and influence of the enantiopure vs. racemic coformer on the physico-chemical properties of a pharmaceutical cocrystal. For that purpose, two new 1:1 cocrystals, namely lidocaine:dl-menthol and lidocaine:d-menthol, were prepared. The menthol racemate-based cocrystal was evaluated by means of X-ray diffraction, infrared spectroscopy, Raman, thermal analysis, and solubility experiments. The results were exhaustively compared with the first menthol-based pharmaceutical cocrystal, i.e., lidocaine:l-menthol, discovered in our group 12 years ago. Furthermore, the stable lidocaine/dl-menthol phase diagram has been screened, thoroughly evaluated, and compared to the enantiopure phase diagram. Thus, it has been proven that the racemic vs. enantiopure coformer leads to increased solubility and improved dissolution of lidocaine due to the low stable form induced by menthol molecular disorder in the lidocaine:dl-menthol cocrystal. To date, the 1:1 lidocaine:dl-menthol cocrystal is the third menthol-based pharmaceutical cocrystal, after the 1:1 lidocaine:l-menthol and the 1:2 lopinavir:l-menthol cocrystals reported in 2010 and 2022, respectively. Overall, this study shows promising potential for designing new materials with both improved characteristics and functional properties in the fields of pharmaceutical sciences and crystal engineering.

BCS Class II drugs, such as itraconazole (ITZ), exhibit poor solubility (1–4 ng/mL) and so require solubility enhancement. Therefore, ITZ and Kollidon® VA64 (KOL) amorphous solid dispersions (ASDs) were produced using hot-melt extrusion (HME) to improve ITZ’s poor solubility. A novel strategy for tablet formulations using five inorganic salts was investigated (KCl, NaCl, KBr, KHCO3 and KH2PO4). These kosmotopric salts are thought to compete for water hydration near the polymer chain, hence, preventing polymer gelation and, therefore, facilitating disintegration and dissolution. Out of all the formulations, the KCl containing one demonstrated acceptable tensile strength (above 1.7 MPa), whilst providing a quick disintegration time (less than 15 min) and so was selected for further formulation development through a design of the experiment approach. Seven ITZ-KOL-ASD formulations with KCl were compacted using round and oblong punches. Round tablets were found to disintegrate under 20 min, whereas oblong tablets disintegrated within 10 min. The round tablets achieved over 80% ITZ release within 15 min, with six out of seven formulations achieving 100% ITZ release by 30 min. It was found that tablets comprising high levels of Avicel® pH 102 (30%) and low levels of KCl (5%) tend to fail the disintegration target due to the strong bonding capacity of Avicel® pH 102. The disintegration time and tensile strength responses were modeled to obtain design spaces (DSs) relevant to both round and oblong tablets. Within the DS, several formulations can be chosen, which meet the Quality Target Product Profile (QTPP) requirements for immediate-release round and oblong tablets and allow for flexibility to compact in different tablet shape to accommodate patients’ needs. It was concluded that the use of inorganic salts, such as KCl, is the key to producing tablets of ITZ ASDs with fast disintegration and enhanced dissolution. Overall, ITZ-KOL-ASD tablet formulations, which meet the QTPP, were achieved in this study with the aid of Quality by Design (QbD) principles for formulation and compaction process development and optimization.

Repaglinide is an oral blood-glucose-lowering drug used to manage type-2 diabetes mellitus by lowering post-prandial glucose by stimulating insulin secretion from pancreatic beta cells. According to the biopharmaceutical classification system, repaglinide falls under the class II category. For such drugs, limited solubility and poor dissolution rate are the major hurdles to overcome by formulation scientists, as they hinder drug absorption and lead to inadequate therapeutic effects. Therefore, this review aims to discuss in depth the various approaches investigated in the past five years to improve the solubility and dissolution of orally administered repaglinide: namely, solid dispersion, co-amorphous technology, cyclodextrin complexation, phospholipid complexes and polymeric micelles, nanocrystals, nanosuspensions and nanofibers.

Aprepitant is the first member of a relatively new antiemetic drug class called NK1 receptor antagonists. It is commonly prescribed to prevent chemotherapy-induced nausea and vomiting. Although it is included in many treatment guidelines, its poor solubility causes bioavailability issues. A particle size reduction technique was used in the commercial formulation to overcome low bioavailability. Production with this method consists of many successive steps that cause the cost of the drug to increase. This study aims to develop an alternative, cost-effective formulation to the existing nanocrystal form. We designed a self-emulsifying formulation that can be filled into capsules in a melted state and then solidified at room temperature. Solidification was achieved by using surfactants with a melting temperature above room temperature. Various polymers have also been tested to maintain the supersaturated state of the drug. The optimized formulation consists of CapryolTM 90, Kolliphor® CS20, Transcutol® P, and Soluplus®; it was characterized by DLS, FTIR, DSC, and XRPD techniques. A lipolysis test was conducted to predict the digestion performance of formulations in the gastrointestinal system. Dissolution studies showed an increased dissolution rate of the drug. Finally, the cytotoxicity of the formulation was tested in the Caco-2 cell line. According to the results, a formulation with improved solubility and low toxicity was obtained.

(1) Background: Solid dispersion (SD) can help increase the bioavailability of poorly water-soluble drugs. Meanwhile, apixaban (APX)—a new anticoagulation drug—has low water solubility (0.028 mg/mL) and low intestinal permeability (0.9 × 10−6 cm/s across Caco-2 colonic cells), thus resulting in a low oral bioavailability of

Through liquid-liquid phase separation (LLPS), it is possible to generate drug-rich nanoparticles during the dissolution of conventional amorphous solid dispersions (ASDs). These self-generated nanoparticles may improve the oral absorption of poorly water-soluble drugs by enhancing the drug's apparent solubility and effective membrane permeability. However, due to the high concentration threshold required for LLPS, conventional ASDs that can consistently generate drug-rich nanoparticles during dissolution are rare. More importantly, the quality of these meta-stable drug-rich nanoparticles is hard to control during dissolution, leading to inconsistency in formulation performances. This work has described a continuous twin-screw extrusion process capable of producing nanosized ASD (NASD) formulations that can offer better solubility and permeability enhancements over conventional ASD formulations. Two polymeric carriers, polyvinylpyrrolidone-co-vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), with a model hydrophobic drug celecoxib (BCS II), were formulated into both ASD and NASD formulations. Compared to the conventional ASD formulation, the prefabricated NASD (sizes ranging between 40 to 200 nm) embedded within a polyol matrix can be rapidly dispersed into a nanoparticle suspension in the presence of aqueous media. The resulting NASDs achieved drug loadings up to 80% w/w and a maximum of 98% encapsulation efficiency. Because of the TSE platform's high drug-loading capacity and high scalability, the developed method may be useful for continuously producing personalized nanomedicines.

Background and objective: Low aqueous solubility of active pharmaceutical ingredients has an effect on both formulation development and bioavailability. Nimodipine is an antihypertensive agent with low oral bioavailability, which might be attributed to the extremely poor water solubility. This study aimed to increase the solubility of nimodipine in water using hydrotropes and solid dispersion technology to increase dissolution rate compared to the marketed drug product. Methods: Solubility of nimodipine was determined separately in sodium acetate, sodium citrate, sodium benzoate, and niacinamide solutions at a concentration of 10, 20, 30, and 40% w/v using distilled water as a solvent. The highest solubility was obtained in 40% sodium benzoate solution. Mixed concentrations of hydrotropic agents were used in ratio 1:3 (niacinamide: sodium benzoate). Fourier-transform infrared spectroscopy was used to exclude any drug-hydrotropes interaction. The dissolution rate of nimodipine from solid dispersion and physical mixture were studied using USP type II dissolution test apparatus in acetate buffer (pH 4.5) as a dissolution media. Results: Hydrotropic solid dispersion of nimodipine with a blend (30% sodium benzoate and 10% niacinamide) increased the dissolution rate of the drug by 1.5 folds compared to the marketed conventional nimodipine tablet. Fourier-transform infrared analysis did not show any physicochemical interaction between drug and carriers in solid dispersion formulation. Conclusion: The hydrotrop is a novel and safe compound. It is a successful way to enhance the solubility of poorly aqueous soluble drugs. Immediate dissolution of practically insoluble drug nimodipine in dissolution media indicates that it has a great potential to solubilize the drug in biological fluids. Thus, a considerable improvement in bioavailability and onset of action of the drug can be predictable. Adding of a hydrotropic agent with nimodipine in solid dispersion increased the dissolution rate of the drug compared to the marketed conventional nimodipine tablet Keywords: Hydrotropes; Nimodipine; Solubility enhancement; Solid dispersion.

Kojic acid (KA) is a BCS class II drug having low solubility and high permeability. This study was designed to enhance the aqueous solubility of KA, as well as its dissolution rate and, in turn, bioavailability, by formulating its smart nanocrystals. Nanocrystals of pure KA were formulated by the top-down method under high-pressure homogenization followed by freeze drying. The nanocrystals were evaluated for stability and other physical characteristics, including zeta sizer analysis, DSC, surface morphology, XRD, drug content, solubility, FTIR and in vitro drug release. The KA nanocrystals were found to be stable when kept at exaggerated conditions. The particle size of the nanocrystals was 137.5 ± 1.7, 150 ± 2.8, and 110 ± 3.0 nm for the F1, F2 and F3 formulations, respectively. There was negative zeta potential for all the formulations. The dispersity index was 0.45 ± 0.2, 0.36 ± 0.4 and 0.41 ± 1.5 for the F1, F2 and F3, respectively. The DSC studies showed that there was no interaction between the KA and the excipients of the nanocrystals. The morphological studies confirmed the presence of rough crystalline surfaces on the nanosized particles. XRD studies showed the successful preparation of nanocrystals. The drug content was in the official range of 90 ± 10%. The solubility of KA was significantly (p < 0.05) enhanced in the formulations of its nanocrystals as compared with pure KA powder. The ATR-FTIR studies revealed the presence of functional groups in both KA and KA-loaded nanocrystals, and no interaction was found between them. The nanocrystals released 83.93 ± 1.22% of KA in 24 h. The study concluded that the nanocrystals were successfully formulated using the top-down method followed by high-pressure homogenization. The solubility, as well as the dissolution, of the KA was enhanced, and this could improve the therapeutic effects of KA.

In this study, we report the highly responsive chitosan-based chemically cross-linked nanomatrices, a nano-version of hydrogels developed through modified polymerization reaction for solubility improvement of poorly soluble drug simvastatin. The developed nanomatrices were characterized for solubilization efficiency, swelling studies, sol-gel analysis, in vitro drug release studies, DSC, FTIR, XRD, SEM, particle size analysis, and stability studies. An in vivo acute toxicity study was conducted on female Winstor rats, the result of which endorsed the safety and biocompatibility of the system. A porous and fluffy structure was observed under SEM analysis, which supports the great swelling tendency of the system that further governs the in vitro drug release. Zeta sizer analyzed the particle size in the range of 227.8 ± 17.8 nm. Nano sizing and grafting of hydrophilic excipients to the nanomatrices system explains this shift of trend towards the enhancement of solubilization efficiency, and, furthermore, the XRD results confirmed the amorphous nature of the system. FTIR and DSC analysis confirmed the successful grafting and stability to the system. The developed nanomatrices enhanced the release characteristics and solubility of simvastatin significantly and could be an effective technique for solubility and bioavailability enhancement of other BCS class-II drugs. Due to enhanced solubility, efficient method of preparation, excellent physico-chemical features, and rapid and high dissolution and bio-compatibility, the developed nanomatrices may be a promising approach for oral delivery of hydrophobic drugs.

Fahad Mehmood Khan,1 Mahmood Ahmad,2 Hafiz Arfat Idrees1 1Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Punjab 63100, Pakistan; 2Faculty of Pharmacy, University of Central Punjab, Punjab 54000, PakistanCorrespondence: Mahmood Ahmad Tel +92 300 9682258Email ma786_786@yahoo.comPurpose: To enhance the solubility and dissolution profile of simvastatin (SIM) through co-crystallization with varying ratios of nicotinamide (NIC) using various co-methods.Materials and Methods: Twelve SIM:NIC co-crystal formulations (F01–F12) were prepared using dry grinding, slurry, liquid-assisted grinding, and solvent-evaporation methods, and their properties compared. Optimized formulations were selected on the basis of dissolution profiles and solubility for in vivo studies. The angle of repose, Carr Index and Hausner ratio were calculated to evaluate flow properties. Differential light scattering (DLS) was used to estimate particle-size distribution. Scanning electron microscopy (SEM) was employed to evaluate surface morphology. Thermal analyses and Fourier-transform infrared (FTIR) spectroscopy were used to determine the ranges of thermal stability and physical interaction of formulated co-crystals. X-ray powder diffraction (XPD) spectroscopy was used to determine the crystalline nature. Solubility and dissolution studies were undertaken to determine in vitro drug-release behaviors.Results: Micromeritic analyses revealed the good flow properties of formulated co-crystals. DLS showed the particle size of co-crystals to be in the nanometer range. SEM revealed that the co-crystals were regular cubes. Thermal studies showed the stability of co-crystals at > 300°C. FTIR spectroscopy revealed minor shifts of various peaks. XPD spectroscopy demonstrated co-crystal formation. The formulations exhibited an improved dissolution profile with marked improvements in solubility. In vivo studies showed a 2.4-fold increase in Cmax whereas total AUC(0–∞) was increased 4.75-fold as compared with that of SIM tablets.Conclusion: Co-crystallization with NIC improved the solubility and dissolution profile and, hence, the bioavailability of the poorly water-soluble drug SIM.Keywords: pharmacokinetics, solubility enhancement, simvastatin, nicotinamide, co-crystal

In the present study piroxicam loaded starch nanoparticles were prepared to enhance the solubility of piroxicam by nanoprecipitation technique. The preparation of nanoparticles was carried out as per central composite experimental design protocol, having concentration of starch and drug as independent variables and particle size and polydispersity index (PdI) as dependent variables. The particle size and PdI of piroxicam loaded starch nanoparticles was found to be between 282-870 nm and 0.339 to 0.772, respectively. After the characterization by FT-IR, TGA, XRD and SEM studies, the optimized batch was evaluated for in-vitro release study, anti-inflammatory activity and anti-oxidant activity. The in-vitro anti-inflammatory activity of piroxicam loaded starch nanoparticles was found to be more than the pure drug piroxicam whereas the anti-oxidant activity of starch is found greater than starch nanoparticles. In-vitro release study showed 98.8% release in 2 h dissolution study following supercase II transport mechanism of drug release.

A large number of hydrophilic and hydrophobic carriers in pharmaceutical excipients are available today which are used for formulation of solid dispersions. Depending on nature of carriers the immediate release solid dispersions and/or controlled release solid dispersions can be formulated. Initially crystalline carriers were used which are transformed into amorphous solid dispersions with enhanced properties. The carriers used previously were mostly synthetic one. Recent trend towards the use of natural carriers have replaced the use of synthetic carriers. This review is the overview of various synthetic, natural, semisynthetic, modified natural hydrophilic carriers used for formulation of solid dispersions.

Solubility and dissolution rate are essential for the oral absorption and thus bioavailability of poorly soluble drugs. Currently, there are various formulation approaches available to overcome issues in solubility and dissolution rate. However, single formulation approach always has its drawback. The purpose of this work was to explore the nano-cocrystal formulation by combining cocrystal and nanocrystal formulation technologies and to optimize the formulation by investigating its dissolution mechanism. A downstream process investigation was also explored to transform the nano-cocrystal formulation into a final oral solid dosage form. Preparation and optimization of nanocrystal formulations with different lab-scale wet milling methods Different laboratory-scale nanocrystal preparation methods were compared as milling efficiency and process attributes. Dual centrifugation milling was considered the most promising method with higher milling efficiency, formulation screening efficiency, and broader controllable process attributes. Applying the dual centrifugation milling method to efficiently screen stabilizers and adjust process parameters, optimized itraconazole nanocrystal stabilized by poloxamer 407 was produced with a mean particle size of 200 nm and PDI 0.2. The nanosuspension was physically stable at 4, 25 and 40 ��C for one month. The optimized nanocrystal formulation exhibited a faster dissolution rate than the physical mixture and raw drug under sink or non-sink conditions in in vitro dissolution study. While compared with commercial product Sporanox��, nanocrystal formulation exhibited faster drug release under sink conditions but lower and limited solubility increment under non-sink conditions. Itraconazole nanocrystal formulation might not exhibit advantageous in vivo behavior compared to the commercial product. A selection of a suitable in vitro dissolution test to evaluate nanocrystal formulation was crucial. In addition, nanocrystalline formulation significantly improved the dissolution rate of poorly soluble APIs, while its increases in solubility were limited. Finally, some other solubilization methods like cocrystal or amorphization could be combined with the nanocrystal approach and utilized to offer a practical approach for delivering orally poorly soluble drugs. Combination of cocrystal and nanocrystal techniques to improve the solubility and dissolution rate of poorly soluble drugs Four itraconazole and indomethacin nano-cocrystals with mean particle diameters of around 450 nm were successfully prepared. Solid-state characterization suggested that by transforming raw drug powder into its cocrystal form is a new strategy for the preparation of nano-formulations which are physically or chemically unstable during wet milling. Furthermore, in situ solubility studies indicated that nano-cocrystals showed remarkably higher solubility and dissolution rate compared to nanocrystals and cocrystals. The maximum kinetic solubility of nano-cocrystals increased with excess conditions until reaches a plateau. The highest increase was obtained with itraconazole-succinic acid nano-cocrystals with a solubility of 263.5 �� 3.9 ��g/mL which is 51.5 and 6.6 times higher than the solubility of itraconazole crystalline and itraconazole-succinic acid cocrystal. The combination of cocrystals and nanocrystals could potentially overcome the limitation of nanocrystals in solubility improvement and the limitation of cocrystal in dissolution rate improvement. Nanocrystal technique efficiently promotes the potential of cocrystal solubilization effect by its superior dissolution rate. This nano-cocrystal formulation expands the drug development strategies of poorly soluble drugs. Itraconazole-succinic acid nano-cocrystals: Kinetic solubility improvement and influence of polymers on controlled supersaturation A systematic experimental investigation was conducted to explore the precipitation inhibition capacity of a range of commonly used precipitation inhibitors (HPMC E5, HPMC E50, HPMCAS, HPC-SSL, PVPK30 and PVPVA64) in itraconazole-succinic acid nano-cocrystal formulation. HPMC E5 achieved greatest extended nano-cocrystals dissolution and maintenance of supersaturation based on specific drug/polymer intermolecular interaction. Dissolved polymer not only increased maximum achievable supersaturation, but also maintained supersaturation for prolonged times, resulting in significantly broadened AUC maxima. The maximum achievable supersaturation was proportional to the dissolution rate which can be modulated by the rate of supersaturation generation (i.e., addition rate or dose). Supersaturation could be prolonged significantly resulting in 2-5-fold increased area under the dissolution curves compared to nano-cocrystals alone. This effect was however limited by a critical excess of undissolved particles with high specific surface area which acted as crystallization seeds resulting in faster precipitation. To achieve higher and sustained supersaturation from nano-cocrystal formulation during dissolution, faster dissolution rate and proper application of precipitation inhibitors were two driving factors. The relationship between particle size, dose and polymer ratio and their synergic impact on the supersaturation must be considered. Generally, these insights and findings would contribute to the design of optimally performing oral solid dosage formulations with incorporated nano-cocrystals. Incorporation of itraconazole nano-cocrystal into granulated or bead-layered solid dosage forms Three downstream processes (wet granulation, spray granulation, and bead layering) were evaluated on the performance of itraconazole-succinic acid nano-cocrystal suspension. Limited by low drug loading and slow dissolution profile, traditional wet granulation was not suitable for downstream processing of nano-cocrystal formulation. Spray granulation and bead layering could increase the drug loading without significantly compromising the rapid dissolution behavior of nano-cocrystal. However, the type of substrate used for spray granulation impacted the dissolution performance from the granules containing nano-cocrystals. Faster dissolution profiles and higher maximum solubility were obtained when the water-soluble substrate was used. While the type of substrate has no impact on the dissolution behavior of beads layered with nano-cocrystals. Furthermore, during the accelerated stability studies, the nano-cocrystal processed by spray granulation was less stable than nano-cocrystal processed by bead layering upon 3 months storage at 40 ��C/75% RH in non-blistered condition. Overall, bead layering was the most suitable method for the downstream process of nano-cocrystal suspensions with the overall performance of a solid product. In conclusion, this entire work indicated that the combination of cocrystals and nanocrystals could potentially overcome the limitation of nanocrystals in solubility improvement and the limitation of cocrystal in dissolution rate improvement. Nano-cocrystal formulations could be optimized with adding specific precipitation inhibitor. Bead layering was a superior downstream process approach for incorporating nano-cocrystals into an oral solid dosage form without compromising release., L��slichkeit und Aufl��sungsgeschwindigkeit sind f��r die orale Absorption und damit f��r die Bioverf��gbarkeit von schwer l��slichen Arzneimitteln von wesentlicher Bedeutung. Derzeit gibt es verschiedene Formulierungsans��tze um Probleme mit L��slichkeit und Aufl��sungsgeschwindigkeit zu ��berwinden. Einzelne Ans��tze haben jedoch jeweils auch Restriktionen. Ziel dieser Arbeit war es, die Nano-Kristall-Formulierung durch die Kombination von Co-Kristall- und Nanokristall-Formulierungstechnologien zu untersuchen und die Formulierung anhand des Aufl��sungsmechanismus zu optimieren. Au��erdem wurde ein nachgeschalteter Prozess beschrieben, um die Nano-Kristallformulierung in eine endg��ltige orale feste Darreichungsform zu ��berf��hren. Herstellung und Optimierung von Nanokristallformulierungen mit verschiedenen Nassmahlverfahren im Laborma��stab Verschiedene Methoden zur Herstellung von Nanokristallen im Laborma��stab wurden hinsichtlich ihrer Mahlleistung und ihrer Prozesseigenschaften verglichen. Die duale Zentrifugation wurde als die vielversprechendste Methode mit h��herer Vermahlungseffizienz, effizienterem Formulierungsscreening und breiter kontrollierbaren Prozesseigenschaften angesehen. Durch effizientes Screening von Stabilisatoren und Optimierung der Prozessparameter wurden mittels dualer Zentrifugation, durch Poloxamer 407 stabilisierte Itraconazol-Nanokristalle mit einer mittleren Partikelgr����e von 200 nm und einem PDI von 0,2 hergestellt. Die Nanosuspension war bei 4, 25 und 40 ��C einen Monat lang physikalisch stabil. Die optimierte Nanokristallformulierung wies in der in-vitro-Aufl��sungsstudie unter Sink- und Nicht-Sink-Bedingungen eine schnellere Aufl��sungsrate auf als die reine Substanz oder die physikalische Mischung . Im Vergleich zum kommerziellen Produkt Sporanox�� zeigte die Nanokristallformulierung eine schnellere Wirkstofffreisetzung unter Sinkbedingungen, aber einen geringeren und begrenzten L��slichkeitszuwachs unter Nicht-Sinkbedingungen. Die Itraconazol-Nanokristallformulierung k��nnte im Vergleich zum kommerziellen Produkt kein verbessertes in-vivo-Verhalten aufweisen. Die Auswahl eines geeigneten in-vitro-Aufl��sungstests ist ein zentraler Punkt zur Bewertung der Nanokristallformulierung. Dar��ber hinaus verbesserte die nanokristalline Formulierung die Aufl��sungsgeschwindigkeit von schwer l��slichen Wirkstoffen erheblich, w��hrend die Erh��hung der L��slichkeit begrenzt war. Schlie��lich k��nnten andere Solubilisierungsmethoden wie co-kristalline oder amorphe Formulierungen mit dem nanokristallinen Ansatz kombiniert und genutzt werden, um einen praktischen Ansatz f��r die orale Verabreichung schwer l��slicher Arzneimittel zu bieten. Kombination von Co-kristall- und Nanokristalltechniken zur Verbesserung der L��slichkeit und Aufl��sungsgeschwindigkeit schwerl��slicher Arzneimittel Vier Itraconazol- und Indomethacin-Nanokristalle mit einem mittleren Partikeldurchmesser von etwa 450 nm wurden erfolgreich hergestellt. Die Festk��rpercharakterisierung deutete darauf hin, dass die Umwandlung des Roharzneimittelpulvers in seine co-kristalline Form eine neue Strategie f��r die Herstellung von Nanoformulierungen darstellt, welche bei Nassmahlung physikalisch oder chemisch instabil w��ren. Dar��ber hinaus zeigten in-situ-L��slichkeitsstudien, dass Nano-Co-kristalle im Vergleich zu Nanokristallen und Co-kristallen eine deutlich h��here L��slichkeit und Aufl��sungsgeschwindigkeit aufweisen. Die maximale kinetische L��slichkeit der Nano-Kristalle nahm mit den ��berschussbedingungen zu, bis sie ein Plateau erreichte. Der h��chste Anstieg wurde bei Itraconazol-Bernsteins��ure-Nanokristallen mit einer L��slichkeit von 263,5 �� 3,9 ��g/ml erzielt, was 51,5- bzw. 6,6-mal h��her ist als die L��slichkeit von kristallinem Itraconazol und Itraconazol-Bernsteins��ure-Co-Kristallen. Die Kombination von Co-Kristallen und Nanokristallen k��nnte die Beschr��nkung von Nanokristallen bei der Verbesserung der L��slichkeit und die Beschr��nkung von Co-Kristallen bei der Verbesserung der Aufl��sungsgeschwindigkeit ��berwinden. Die Nanokristalltechnik f��rdert effizient das Potenzial der Solubilisierung von Co-Kristallen durch ihre ��berlegene Aufl��sungsgeschwindigkeit. Eine Nanokristallformulierung erweitert die Strategien der Arzneimittelentwicklung f��r schwerl��sliche Arzneimittel. Itraconazol-Bernsteins��ure-Nanokristalle: Verbesserung der kinetischen L��slichkeit und Einfluss der Polymere auf die kontrollierte ��bers��ttigung Es wurde eine systematische experimentelle Untersuchung durchgef��hrt, um die Ausf��llungsinhibitionskapazit��t einer Reihe von ��blicherweise verwendeten Ausf��llungsinhibitoren (HPMC E5, HPMC E50, HPMCAS, HPC-SSL, PVPK30 und PVPVA64) in Itraconazol-Bernsteins��ure-Nanokristallformulierungen zu erkunden. Speziell HPMC E5 verl��ngerte die Aufl��sung der Nano-Kristalle und die Aufrechterhaltung der ��bers��ttigung aufgrund der spezifischen intermolekularen Wechselwirkung zwischen Arzneimittel und Polymer. Das aufgel��ste Polymer erh��hte nicht nur die maximal erreichbare ��bers��ttigung, sondern hielt die ��bers��ttigung auch ��ber einen l��ngeren Zeitraum aufrecht, was zu einer signifikanten Verbreiterung der AUC-Maxima f��hrte. Die maximal erreichbare ��bers��ttigung war proportional zur Aufl��sungsrate, die durch die Rate der ��bers��ttigungserzeugung (Zugaberate oder Dosis) moduliert werden kann. Die ��bers��ttigung konnte hierdurch deutlich verl��ngert werden, was zu einer 2-5-fachen Vergr����erung der AUC im Vergleich zu Nanokristallen allein f��hrte. Dieser Effekt wurde jedoch durch einen kritischen ��berschuss an ungel��sten Partikeln mit hoher spezifischer Oberfl��che begrenzt, die als Kristallisationskeime fungierten und zu einer schnelleren Ausf��llung f��hrten. Um eine h��here und anhaltende ��bers��ttigung der Nanokristallformulierung w��hrend der Aufl��sung zu erreichen, waren eine schnellere Aufl��sungsrate und die richtige Anwendung von Ausf��llungsinhibitoren zwei entscheidende Faktoren. Die Beziehung zwischen Partikelgr����e, Dosis und Polymerverh��ltnis und ihre synergetischen Auswirkungen auf die ��bers��ttigung m��ssen ber��cksichtigt werden. Generell w��rden diese Erkenntnisse und Ergebnisse zur Entwicklung optimal funktionierender oraler fester Dosierungsformulierungen mit eingearbeiteten Nanokristallen beitragen. Einarbeitung von Itraconazol-Bernsteins��ure-Nanokristallen in granulierte oder wirkstoffbeschichtete feste Darreichungsformen Drei nachgeschaltete Verfahren (Nassgranulierung, Spr��hgranulierung und Perlenschichtung) wurden hinsichtlich der Leistung der Itraconazol-Bernsteins��ure Nanokristallsuspension bewertet. Aufgrund der geringen Wirkstoffbeladung und des langsamen Aufl��sungsprofils war die herk��mmliche Nassgranulation f��r die nachgeschaltete Verarbeitung der Nano-Kristallformulierung nicht geeignet. Durch Spr��hgranulation und Coating konnte die Wirkstoffbeladung erh��ht werden, ohne das schnelle Aufl��sungsverhalten der Nanokristalle wesentlich zu beeintr��chtigen. Die Art des f��r die Spr��hgranulation verwendeten Substrats wirkte sich jedoch auf die Aufl��sungsleistung der Nanokristalle enthaltenden Granulate aus. Schnellere Aufl��sungsprofile und eine h��here maximale L��slichkeit wurden erzielt, wenn ein wasserl��sliches Substrat verwendet wurde. Die Art des Substrats hatte jedoch keinen Einfluss auf das Aufl��sungsverhalten der mit Nanokristallen beschichteten Perlen. In den beschleunigten Stabilit��tsstudien waren die durch Spr��hgranulation hergestellten Nanokristalle nach dreimonatiger Lagerung bei 40 ��C und 75 % relativer Luftfeuchtigkeit weniger stabil als die durch Coating hergestellten Nanokristalle. Insgesamt war die Perlenschichtung die am besten geeignete Methode f��r die Weiterverarbeitung von Nano-Kristallsuspensionen in eine finale feste Darreichungsform. Zusammenfassend l��sst sich sagen, dass die Kombination von Co-Kristallen und Nanokristallen die Beschr��nkung von Nanokristallen bei der Verbesserung der L��slichkeit und die Beschr��nkung von Co-Kristallen bei der Verbesserung der Aufl��sungsgeschwindigkeit ��berwinden k��nnte. Nano-Kristall-Formulierungen k��nnten durch Zugabe eines spezifischen Ausf��llungsinhibitors optimiert werden. Die Perlenschichtung war ein ��berlegener nachgeschalteter Prozessansatz, um Nano-Kristalle in eine feste orale Darreichungsform einzubringen, ohne die Freisetzung zu beeintr��chtigen.

PROteolysis TArgeting Chimaeras (PROTACs) offer new opportunities in modern medicine by targeting proteins that are undruggable to classic inhibitors. However, due to their hydrophobic structure, PROTACs typically suffer from low solubility, and oral bioavailability remains challenging. At the same time, due to their investigative state, the drug supply is meager, leading to limited possibilities in terms of formulation development. Therefore, we investigated the solubility enhancement employing mini-scale formulations of amorphous solid dispersions (ASDs) and liquisolid formulations of the prototypic PROTAC ARCC-4. Based on preliminary supersaturation testing, HPMCAS (L Grade) and Eudragit® L 100-55 (EL 100-55) were demonstrated to be suitable polymers for supersaturation stabilization of ARCC-4. These two polymers were selected for preparing ASDs via vacuum compression molding (VCM), using drug loads of 10 and 20%, respectively. The ASDs were subsequently characterized with respect to their solid state via differential scanning calorimetry (DSC). Non-sink dissolution testing revealed that the physical mixtures (PMs) did not improve dissolution. At the same time, all ASDs enabled pronounced supersaturation of ARCC-4 without precipitation for the entire dissolution period. In contrast, liquisolid formulations failed in increasing ARCC-4 solubility. Hence, we demonstrated that ASD formation is a promising principle to overcome the low solubility of PROTACs.

Poly(2-hydroxyethylmethacrylate)/Naproxen (NPX/pHEMA) and poly (2-hydroxypropyl methacrylate)/Naproxen (NPX/pHPMA) composites with different NPX content were prepared in situ by free radical photopolymerization route. The resulted hybrid materials were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), scanning Electron microscopy (SEM), and X-ray diffraction (XRD). These composites have been studied as drug carrier systems, in which a comparison of the in vitro release dynamic of NPX between the two drug carrier systems has been conducted. Different factors affecting the performance of the release dynamic of this drug, such as the amount of Naproxen incorporated in the drug carrier system, the pH of the medium and the degree of swelling, have been investigated. The results of the swelling study of pHEMA and pHPMA in different media pHs revealed that the diffusion of water molecules through both polymer samples obeys the Fickian model. The “in vitro” study of the release dynamic of Naproxen from NPX/pHEMA and NPX/pHPMA drug carrier systems revealed that the higher percentage of NPX released was obtained from each polymer carrier in neutral pH medium, and the diffusion of NPX trough these polymer matrices also obeys the Fickian model. It was also found that the less the mass percent of NPX in the composites, the better its release will be. The comparison between the two drug carrier systems revealed that the pHEMA leads to the best performance in the release dynamic of NPX. Regarding Naproxen solubility in water, the results deducted from the “in vitro” study of NPX/pHEMA10 and NPX/pHPMA10 drug carrier systems revealed a very significant improvement in the solubility of NPX in media pH1 (2.33 times, 1.43 times) and 7 (3.32 times, 2.60 times), respectively, compared to those obtained by direct dissolution of Naproxen powder.

Enabling formulations often depend on functional excipients. However, the question remains whether excipients regarded as standard establish similar interactions and subsequently improvement of solubility when employed at unusual manufacturing process conditions. In this study, compaction of API under high pressure in the presence of hydrophilic excipients is proposed as a technique to improve the solubility and/or dissolution rate with an acceptable preservation of the supersaturation state. Binary mixtures of ibuprofen (IBU) with hydroxypropyl cellulose, isomalt, mannitol and sorbitol were compacted applying high pressure (500 MPa) with and without a previous co-milling step. Intrinsic dissolution rate (IDR) was selected to characterize and evaluate dissolution performance. The IDR of neat IBU increased from 5 to 88 fold and the aqueous solubility in the range of 3 to 54%. Regarding the polyols isomalt showed the highest impact on solubility and dissolution, without changing the crystallinity of IBU independent of a co-milling step. Even higher impact was achieved in combination with HPC. However, only without a previous co-milling step, ibuprofen remained crystalline, while co-milling induced an amorphous IBU-content of 38%. Based on XRPD and DSC findings, higher IDR and solubility values correlated with crystal modifications as well as IBU/excipient interactions., Graphical abstract Unlabelled Image

Developing multicomponent crystal forms, especially cocrystals and salts, is becoming a promising pathway to improve the solubility and bioavailability of drugs. Herein, new multicomponent crystals of SHR0302, a new generation of Janus Kinase (JAK) inhibitor that suffers from poor solubility, were developed based on a cooperative approach of computational and experimental coformer screenings. Virtual screening methods, including the conductor-like screening model for realistic solvents (COSMO-RS) and molecular complementary (MC) analysis, were employed to predict the binding affinity between SHR0302 and selected coformers. The developed screening method was capable of reducing the screening database to 30 coformers from a total of 42 proposed coformers. The proof-of-concept experimental screening study was performed to demonstrate the efficiency of computational screening, wherein three new multicomponent crystalline forms were found and fully characterized by powder X-ray diffraction, thermal analysis, and IR and 1H-NMR spectroscopy. Further, the measurements of the solubility property of these new multicomponent crystal forms reveal an apparent promotion compared with the drug alone. Finally, the receiver operator characteristic (ROC) curve was used to assess the prediction performance of the COSMO-RS model. It was found that the established screening model can effectively shorten the experimental screening time and efforts.

Hot melt extrusion offers an efficient way of increasing the solubility of a poorly soluble drug. Shellac has potential as a pharmaceutical matrix polymer that can be used in this extrusion process, with further advantages for use in enteric drug delivery systems. The rheological property of a material affects the extrusion process conditions. However, the literature does not refer to any published work that investigates the processability of various shellac materials. This work explores various types of shellac and explores their physicochemical and thermal properties along with their processability in the hot melt extrusion application. Physicochemical characterization of the materials was achieved using differential scanning calorimetry, Fourier transform infrared spectroscopy, scanning electron microscopy and energy-dispersive X-ray spectroscopy. Additional processability characterization was achieved using melt flow index and rheology analysis. The results indicated that there was no chemical difference between the various shellac types compared in this study. However, the extrudable temperature ranges and rheological properties of different shellac types varied, SSB 55 Pharma FL had the lowest processing temperature and glass transition temperatures. Due to the shear-thinning behaviours, shellac can be extruded at lower temperatures. This study provides necessary data to determine the processing conditions in hot melt extrusion applications for the range of shellac materials.

Nanocrystals are carrier-free, submicron-sized, colloidal drug delivery systems with particle sizes in the mean nanometer range. Nanocrystals have high bioavailability and fast absorption because of their high dissolution velocity and enhanced adhesiveness to cell membranes. Loxoprofen, a nonsteroidal anti-inflammatory drug belonging to the Biopharmaceutical Classification System (BCS) II drug class, was selected as the model drug. The aim of this study was to formulate nanocrystals of loxoprofen. A total of 12 formulations (F1 to F12) were prepared. An antisolvent technique was used to determine the effects of various stabilizers and processing conditions on the optimization of formulations. The various stabilizers used were hydroxypropyl methylcellulose (0.5%), polyvinylpyrrolidone (0.5%), and sodium lauryl sulfate (0.1%). The various characterizations conducted for this research included stability studies at 25 °C and 4 °C, scanning electron microscopy, transmission electron microscopy (TEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), zeta potentials, polydispersity indexes, and dissolution studies. F10 was the optimized formulation that showed stability at room temperature, as well as at a refrigerated temperature, for 30 days. A high dissolution rate (100% within the first 10 min) was shown by comparative dissolution studies of nano-suspensions with the micro-suspension and raw loxoprofen. F10 formulation had a non-porous and crystalline morphology on evaluation by TEM and XRPD, respectively, and the average particle size was 300 ± 0.3 nm as confirmed by TEM. DSC recorded a reduction in the melting point (180 °C processed and 200 °C unprocessed melting points). The dissolution rate and solubility of the formulated loxoprofen nanocrystals were significantly enhanced. It can be concluded that selecting suitable stabilizers (i.e., polymers and surfactants) can produce stable nanocrystals, and this can potentially lead to a scaling up of the process for commercialization.

This research demonstrates the influence of laser speed and the drug particle size on the manufacturing of amorphous solid dispersions (ASD) and dosage forms thereof using selective laser sintering 3-dimensional (3D) printing. One-step manufacturing of ASD is possible using selective laser sintering 3D printing processes, however, the mechanism of ASD formation by this process is not completely understood and it requires further investigation. We hypothesize that the mechanism of ASD formation is the diffusion and dissolution of the drug in the polymeric carrier during the selective laser sintering (SLS) process and the drug particle size plays a critical role in the formation of said ASDs as there is no mixing involved in the sintering process. Herein, indomethacin was used as a model drug and introduced into the feedstock (Kollidon® VA64 and Candurin® blend) as either unprocessed drug crystals (particle size &gt, 50 µm) or processed hot-melt extruded granules (DosePlus) with reduced drug particle size (&lt, 5 µm). These feedstocks were processed at 50, 75, and 100 mm/s scan speed using SLS 3D printing process. Characterization and performance testing were conducted on these tablets which revealed the amorphous conversion of the drug. Both MANOVA and ANOVA analyses depicted that the laser speed and drug particle size significantly impact the drug’s apparent solubility and drug release. This significant difference in performance between formulations is attributed to the difference in the extent of dissolution of the drug in the polymeric matrix, leading to residual crystallinity, which is detrimental to ASD’s performance. These results demonstrate the influence of drug particle size on solid-state and performance of 3D printed solid dispersions, and, hence, provide a better understanding of the mechanism and limitations of SLS 3D printing of ASDs and its dosage forms.

Nano-crystallization is a new emerging strategy to promote the saturation solubility, dissolution rate and subsequent bioavailability of Biopharmaceutical Class II drugs. Capsaicin belongs to BCS class-II drugs having low water solubility and dissolution rate. Nano-crystals (NC) of pure Capsaicin was developed and optimized in order to increase its water solubility, dissolution and further to promote its adhesiveness to skin epidermis layer. NC formulations were subjected to stability studies, droplet size, surface charge, poly-dispensability index, drug content, entrapment efficiency, thermal analysis, surface morphology, crystalline studies, solubility profile, in vitro release and ex vivo permeation studies. In vivo anti-inflammatory assay (Carrageenan-induced paw edema) was performed in Sprague Dawley rats. Nanocrystals loaded with capsaicin showed particle size 120 ± 3.0 nm with surface charge of −20.7 ± 3.5 and PDI was 0.48 ± 1.5. Drug content and entrapment efficiency of T3 was 85% and 90 ± 1.9% respectively. Thermal studies predicted that melting peak of capsaicin was present in the formulation suggested that there was no interaction between active moieties and excipients in NC formulation. Surface morphology confirmed the presence of Nano-size crystals having rough crystalline surface. XRD proved that the capsaicin NC are successfully developed by using high speed homogenization. The solubility of capsaicin was found to be 12.0 ± 0.013 μg/mL in water. In vitro study revealed that 89.94 ± 1.9% of drug was released within 24 h. Similarly, drug permeation was 68.32 ± 1.83%, drug retained in skin was 16.13 ± 1.11% while drug retained on skin was 9.12 ± 0.14% after 12 h. The nanocrystals showed higher anti-inflammatory activity as compared to marketed product (Dicloran®). The study concluded that improvement in dissolution rate of capsaicin may potentially provide the opportunities in the development of a much cost-effective dosage forms that will produce improved pharmacological effects, but at low dose as compared to the already available products.

Ibuprofen, a weakly acidic non-steroidal anti-inflammatory drug having poor aqueous solubility, is a challenging drug for the development of pharmaceutical formulations, resulting in numerous research attempts focusing on improvement of its solubility and consequently bioavailability. Most studies have been done for solid dosage forms, with very little attention paid to parenterals. Hence, the main purpose of the present study was to enhance ibuprofen solubility as a result of formulation composition and the freeze drying process. Moreover, the purpose was to prepare a freeze dried dosage form with improved ibuprofen solubility that could, after simple reconstitution with water for injection, result in an isotonic parenteral solution. Solubility of ibuprofen was modified by various excipients suitable for parenteral application. Drug interactions with selected excipients in the final product/lyophilisate were studied by a combined use of XRPD, DSC, Raman and ss-NMR. Analyses of lyophilized samples showed solubility enhancement of ibuprofen and in situ formation of an ibuprofen salt with the alkaline excipients used.

Amorphization, typically in the form of amorphous solid dispersion (ASD), represents a well-established solubility enhancement strategy for poorly soluble drugs. Recently, two amorphous drug formulations, i.e., the amorphous drug–polyelectrolyte nanoparticle complex (nanoplex) and co-amorphous system, have emerged as promising alternatives to circumvent the issues faced by ASD (i.e., large dosage requirement, high hygroscopicity). In the present work, the nanoplex was benchmarked against the co-amorphous system in terms of the preparation efficiency, drug payload, thermal stability, dissolution rate, supersaturation generation, and accelerated storage stability. Weakly acidic curcumin (CUR) and weakly basic ciprofloxacin (CIP) were used as the model poorly soluble drugs. The CUR and CIP nanoplexes were prepared using chitosan and sodium dextran sulfate as the polyelectrolytes, respectively. The co-amorphous CUR and CIP were prepared using tannic acid and tryptophan as the co-formers, respectively. The benchmarking results showed that the amorphous drug nanoplex performed as well as, if not better than, the co-amorphous system depending on the drug in question and the aspects being compared. The present work successfully established the nanoplex as an equally viable amorphous drug formulation as the more widely studied co-amorphous system to potentially serve as an alternative to ASD.

Tese no âmbito do Doutoramento em Ciências Farmacêuticas, ramo de Tecnologia Farmacêutica, apresentada à Faculdade de Farmácia da Universidade de Coimbra. Solid dispersions are systems where one component is dispersed in a carrier, and the whole system is solid. The solubility, drug release, chemical and physical stability, and in vivo performance of these compositions vary depending on the chemical characteristics of the main components and the physical structure of the composition. Solid dispersions are considered one of the most complex pharmaceutical systems, and an in-depth understanding of their properties is essential to control and modulate product performance. The use of Hot-melt extrusion (HME) to prepare solid dispersions has made it a technology that changed the entire paradigm of the pharmaceutical industry research and manufacturing. It is recognizably able to overcome formulation barriers and tailor drug performance and has been used successfully for already marketed products and many others under development. The enhancement of solubility is the primary use of HME, but others include taste-masking, stabilization of amorphous drugs, and controlled drug delivery. In this work, HME technology was applied in three different scopes, particularly in the solubility enhancement of a poorly soluble compound, in the physical stabilization of an unstable amorphous drug, and in the controlled release of a highly soluble drug in low drug load. A combination of chromatographic (high and ultra performance liquid chromatography (HPLC and UPLC)), microscopic (optical microscopy, polarized light microscopy (PLM), scanning electron microscopy (SEM)), thermal (standard differential scanning calorimetry (DSC), modulated temperature DSC (mDSC), thermogravimetric analysis (TGA), and polarized light thermal microscopy (PLTM)), diffraction (X-ray powder diffraction (XRPD)), and spectroscopic techniques (Raman spectroscopy coupled to confocal microscopy, or in some cases to variable temperature) were used. Dissolution testing and stability studies were as well crucial for the in-depth characterization of the prepared systems. High-throughput screening methods, thermodynamic predictions, and statistical analysis were also of great importance. In this work, a systematic step-by-step methodology for the development of solid dispersions was presented, where thermodynamics, screening approaches, multivariate statistics, and process optimization were combined (Chapter I). It was focused on pharmaceutical development under the Quality by Design principles and practical methods from early development to regulatory approval. The technical and scientific specificities of HME-based formulations were discussed in line with the state of the art of product development and current regulatory guidance. Then, an amorphous solid dispersion (ASD) of Etravirine was prepared to enhance the solubility of this poorly soluble drug (Chapter II). An extensive investigation of the solubilization capacity and physical stability of different compositions was performed, where theoretical predictions, high-throughput screening, and Principal Components Analysis were combined. The dissolution rate was improved more than two times, and the ASD demonstrated to be physically and chemically stable for at least three months, even when stored at accelerated conditions. Although not expected, it was later explained by Raman spectroscopy, where molecular interactions affecting the CN groups of Etravirine were observed. Moreover, Raman's high potential to distinguish solid-state forms was demonstrated, including differentiating amorphous and crystalline states. A different aim of the investigation was described in the Ibrutinib research (Chapter III), where HME was applied to improve the physical stability of the amorphous drug. Although with a high tendency to convert into the most stable crystalline form, stability until at least six months at accelerated conditions was achieved through HME in a very high drug load of 50%. Intermolecular interactions characterized by thermal analysis and Raman spectroscopy involving the α, β unsaturated ketone of ibrutinib supported the physical strength of the prepared systems. This application of HME technology is not common but demonstrated a remarkable interplay between HME, drug loading, polymeric carriers, solid state, and intermolecular interactions that can also be applied to other drugs. Lastly, the well-known technological challenge of controlling the release of a highly soluble drug was overcome through an innovative platform involving HME (Chapter IV). The selected prototype is not standard in the field and consists of microtablets tableted into tablets, where HME is coupled with double compression as downstream processing. Its performance was exhaustively characterized, and near zero-order kinetics for 6 to 8 hours observed on dissolution. The mechanistic drug release was explored through the Weibull function and SEM, and revealed a combination of swelling, diffusion, and erosion. The research performed had several goals, but it is possible to stand out the overcome of formulation barriers, tailoring challenging drug properties through the use of the potentialities of HME. Also important is the contribution to an improved understanding of the complex solid-state characterization of solid dispersions, including physicochemical properties of drugs and formulated systems. However, further efforts and expertise are still required to achieve the purpose of this work. The research identified gaps, challenges, and future areas of study to, finally, take these products - better products - to market. As dispersões sólidas são sistemas em que um determinado componente está disperso num veículo, e o sistema existe no estado sólido. A solubilidade, dissolução do fármaco, estabilidade física e química, e comportamento in vivo destas formulações varia consoante as características químicas dos componentes principais e a estrutura física da composição. As dispersões sólidas são consideradas um dos tipos de sistemas farmacêuticos mais complexo, e a caracterização profunda das suas propriedades é essencial para controlar e modular o comportamento do produto. O uso da extrusão a quente fez com que o paradigma da investigação e fabrico na indústria farmacêutica fosse completamente alterado no que concerne à preparação de dispersões sólidas. Esta tecnologia é reconhecidamente capaz de ultrapassar barreiras de formulação e modular a performance de fármacos, e tem sido utilizada com sucesso em produtos já comercializados e muitos outros em desenvolvimento. A utilização principal da extrusão a quente é a melhoria da solubilidade, mas pode ser também aplicada para mascarar o sabor, estabilizar fármacos amorfos ou para a libertação controlada de substâncias ativas. Neste trabalho, a tecnologia de extrusão a quente foi aplicada em três contextos diferentes, nomeadamente, na melhoria de solubilidade de um fármaco pouco solúvel, na estabilização do estado físico de uma substância amorfa reconhecidamente instável, e na libertação controlada de um composto altamente solúvel e de baixa dosagem. Para isso, foi utilizada uma combinação de técnicas cromatográficas (cromatografia líquida de alta e ultra eficiência (HPLC e UPLC)), microscópicas (microscopia ótica, microscopia de luz polarizada (PLM), microscopia eletrónica de varrimento (SEM)), térmicas (calorimetria diferencial de varrimento convencional (DSC) e com modulação de temperatura (mDSC), análise termogravimétrica (TGA), e microscopia térmica com luz polarizada (PLTM)), difração (difração de raios X de pó (XRPD)), e espectroscópicas (espectroscopia Raman acoplada a microscopia confocal e combinada, em alguns casos, com variação de temperatura). Os ensaios de dissolução e estudos de estabilidade foram também críticos para a caracterização detalhada dos sistemas preparados. Os métodos de rastreio de alto rendimento, os cálculos termodinâmicos e a análise estatística foram também importantes para o sucesso da investigação. Neste trabalho, foi apresentada uma metodologia sistemática passo-a-passo para o desenvolvimento de dispersões sólidas, onde se combinou a termodinâmica, as estratégias de rastreio, a estatística multivariada e a otimização de processos (Capítulo I). O foco foi o desenvolvimento farmacêutico segundo os princípios de Quality by Design e abordagens práticas, desde os primeiros estudos de desenvolvimento até à aprovação regulamentar. As especificidades técnica e científica das formulações baseadas em extrusão a quente foram discutidas, em linha com o estado da arte do desenvolvimento de produtos farmacêuticos e atuais diretrizes regulamentares. Posteriormente, foi preparada uma dispersão sólida amorfa (ASD) de Etravirina, para melhorar a solubilidade deste fármaco considerado pouco solúvel (Capítulo II). Foi feita uma investigação extensiva da capacidade de solubilização e estabilidade física de composições diferentes, onde se combinaram cálculos termodinâmicos, com o rastreio de alto rendimento e a análise de componentes principais. A taxa de dissolução foi melhorada mais de duas vezes, e a dispersão amorfa demonstrou ser física e quimicamente estável por, pelo menos, três meses, mesmo quando armazenada em condições aceleradas de envelhecimento. Este resultado foi explicado posteriormente através da espectroscopia Raman, onde foram observados sinais de interações intermoleculares nos grupos CN da Etravirina. Foi ainda demonstrado o alto potencial da espectroscopia Raman para distinguir diferentes estados sólidos, nomeadamente para diferenciar o estado amorfo do cristalino. Na investigação aplicada ao Ibrutinib (Capítulo III), o alvo da análise foi distinto e a extrusão foi aplicada para melhorar a estabilidade física de um fármaco no estado amorfo. Apesar de apresentar uma tendência elevada para conversão para o estado cristalino mais estável, foi possível atingir seis meses de estabilidade em condições aceleradas através do uso da extrusão a quente, mesmo utilizando uma elevada quantidade de fármaco na formulação, 50%. A análise térmica e espectroscópica permitiu detetar interações intermoleculares na cetona α, β-insaturada do Ibrutinib, que justificam a resiliência física dos sistemas preparados. Esta aplicação da extrusão não é comum, mas permitiu estabelecer uma relação notável entre extrusão a quente, quantidade de fármaco, excipientes, estado físico e interações intermoleculares, que poderão ser aplicadas a outros compostos. Por último, um conhecido desafio da tecnologia farmacêutica - a libertação de um fármaco muito solúvel em baixa dosagem - foi também ultrapassado, através da criação de uma plataforma tecnológica inovadora baseada na extrusão a quente (Capítulo IV). O protótipo selecionado não é considerado padrão na área, e consiste em microcomprimidos num comprimido, onde a extrusão é acoplada a jusante a uma dupla compressão. O comportamento deste sistema foi exaustivamente caracterizado, tendo-se observado, em dissolução, uma cinética próxima de ordem-zero durante 6 a 8 horas. O mecanismo de libertação foi também explorado através da função de Weibull e SEM, revelando a combinação de intumescimento, difusão e erosão. A investigação realizada teve vários objetivos, destacando-se a transposição de barreiras de formulação, através da modulação de fármacos difíceis recorrendo às potencialidades da extrusão a quente. Não menos importante, contribuiu para uma melhor compreensão da caracterização complexa do estado sólido de dispersões sólidas, incluindo propriedades físico-químicas de fármacos e seus sistemas formulados. No entanto, ainda se verifica a necessidade de esforço e especialização adicionais, de modo que seja atingido o desígnio deste trabalho. Foi possível identificar lacunas, desafios e eventuais áreas de investigação futura para, finalmente, levar os produtos - melhores produtos - até ao mercado. Bluepharma - Indústria Farmacêutica, S.A. (Portugal)

Niclosamide (NIC), a conventional anthelmintic agent, is emerging as a repurposed drug for COVID-19 treatment. However, the clinical efficacy is very limited due to its low oral bioavailability resulting from its poor aqueous solubility. In the present study, a new hybrid drug delivery system made of NIC, montmorillonite (MMT), and Tween 60 is proposed to overcome this obstacle. At first, NIC molecules were immobilized into the interlayer space of cationic clay, MMT, to form NIC–MMT hybrids, which could enhance the solubility of NIC, and then the polymer surfactant, Tween 60, was further coated on the external surface of NIC–MMT to improve the release rate and the solubility of NIC and eventually the bioavailability under gastrointestinal condition when orally administered. Finally, we have performed an in vivo pharmacokinetic study to compare the oral bioavailability of NIC for the Tween 60-coated NIC–MMT hybrid with Yomesan®, which is a commercially available NIC. Exceptionally, the Tween 60-coated NIC–MMT hybrid showed higher systemic exposure of NIC than Yomesan®. Therefore, the present NIC–MMT–Tween 60 hybrid can be a potent NIC drug formulation with enhanced solubility and bioavailability in vivo for treating Covid-19.

Clinical use of 4-Allylpyrocatechol (APC), a potential antifungal agent from Piper betle, is limited because of its low water solubility. The current study explores the development of the self-nanoemulsifying drug delivery system (SNEDDS) containing APC (APC-SNEDDS) to enhance APC solubility. Results demonstrated that excipient type and concentration played an important role in the solubility of APC in the obtained SNEEDS. SNEDDS, comprising 20% Miglyol 812N, 30% Maisine 35-1, 40% Kolliphor RH40, and 10% absolute ethanol, provided the highest loading capacity and significantly increased water solubility of APC. Oil-in-water nanoemulsions (NE) with droplet sizes of less than 40 nm and a narrow size distribution were obtained after dispersing this APC-SNEDDS in water. The droplets had a negative zeta potential between &minus, 10 and &minus, 20 mV. The release kinetics of APC from APC-SNEDDS followed the Higuchi model. The NE containing 1.6 mg APC/mL had effective activity against Candida albicans with dose-dependent killing kinetics and was nontoxic to normal cells. The antifungal potential was similar to that of 1 mg nystatin/mL. These findings suggest that APC-SNEDDS are a useful system to enhance the apparent water solubility of APC and are a promising system for clinical treatment of oral infection caused by C. albicans.

For the past 40 years, praziquantel (PZQ) has been the standard treatment for schistosomiasis, the neglected parasitic disease that affects more than 250 million people worldwide. However, there is no adequate paediatric formulation on the market, leading to off-label use and the division of commercial tablets for adults. This thesis focused on the development of a PZQ formulation based on solid amorphous dispersion (ASD) to solve physicochemical (low water solubility) and sensory (bitter taste) of PZQ active pharmaceutical ingredient (API) disadvantages. ASD with 35 to 50 w/w% API (binary and ternary systems) were produced by hot-melt extrusion (HME) using vinylpyrrolidone-vinyl acetate copolymer (Kollidon® VA 64) as a polymeric carrier. The binary systems consisted of PZQ and Kollidon® VA 64. To rationally develop ASD highly loaded with PZQ, the first study of this thesis focused on the construction of a PZQ- Kollidon® VA 64 phase diagram, constructed from a thermal study of the recrystallization of a supersaturated ASD (50 % PZQ), generated by spray drying. The ternary systems were formulated with a surfactant as an additional component (5 w/w%), using two different types (Span ™ 20 and Kolliphor® SLS). Several techniques were used to characterize the produced ASD (PZQ content, thermal properties, particle morphology, apparent solubility, dissolution profile, and physical stability). All binary and ternary ASD increased the PZQ apparent solubility, more specifically, 70 % to 90 % more than the equilibrium concentration in water at 37°C. The dissolution kinetics was also improved, for example, 90 % of drug release in one hour for the ternary ASD containing SPAN 20 as a surfactant and 35 wt% of API. The second challenge is to mask the bitter taste of PZQ. Taste masking assessments (in vivo and in vitro) and pharmacokinetics studies were performed with selected formulations. Positive results related to masking the bitter taste for both PZQ load (50 and 35 wt%) could be demonstrated. The third challenge for paediatric PZQ is the need of accurate dose adjustment. As an alternative to overcome the challenge of adjusting the doses of a paediatric medicine based on PZQ for children, the use of 3D printing technology (FDM) with direct feeding of powdered amorphous solid dispersions was proposed. We could demonstrate the feasibility of obtaining printlets with two different doses of PZQ (100 and 150 mg) using ternary ASD. The printlets containing 35 wt% of API load and SPAN 20 showed the best dissolution performance. This work demonstrated the interest of ternary ASD containing PZQ in the form of pellets or powder for compressed 3D printing. The main obstacles in the formulation of PZQ, such as low drug solubility, inappropriate taste, and high and variable dosage requirements, can be overcome using the combination of different technologies (production of ASD by HME and FDM as SD printing technology)., Depuis 40 ans, le praziquantel (PZQ) est le traitement standard de la schistosomiase, une maladie parasitaire négligée qui touche plus de 250 millions de personnes dans le monde. Cependant, il n'existe pas de formulation pédiatrique adéquate sur le marché, ce qui conduit à une utilisation hors indication et à la division des comprimés commerciaux pour les adultes. Cette thèse s’articule autour du développement d'une dispersion amorphe solide (ASD) pour le PZQ afin d’améliorer certaines caractéristiques physico-chimiques (faible solubilité dans l'eau) et sensoriels (goût amer) de cet API. Des ASD contenant 35 à 50 % en masse d'API (systèmes binaires et ternaires) ont été produites par extrusion à chaud (HME) en utilisant un copolymère vinylpyrrolidone-acétate de vinyle (Kollidon® VA 64) comme support polymère. Les systèmes binaires sont constitués de PZQ et de Kollidon® VA 64. Afin de développer rationnellement des ASD hautement chargées en PZQ, la première étude de cette thèse porte sur la construction d'un diagramme de phase PZQ- Kollidon® VA 64, construit à partir d'une étude thermique de la recristallisation d'une ASD sursaturé (50 % PZQ), générée par séchage par pulvérisation. Les systèmes ternaires ont été formulés avec un tensioactif comme composant supplémentaire (5 % en masse), en utilisant deux types différents (Span ™ 20 et Kolliphor® SLS). Plusieurs techniques ont été utilisées pour caractériser les ASD produites (teneur en PZQ, propriétés thermiques, morphologie des particules, solubilité apparente, profil de dissolution et stabilité physique). Les ASD binaires et ternaires augmentent la solubilité apparente de la PZQ, plus précisément de 70 % à 90 % par rapport à la concentration d'équilibre dans l'eau à 37 °C. La cinétique de dissolution a également été améliorée, par exemple, 90 % de libération du médicament en une heure pour l’ASD ternaire contenant du SPAN 20 comme surfactant et 35 % en masse d'API. Le deuxième défi consiste à masquer le goût amer du PZQ. Des évaluations du masquage du goût (in vivo et in vitro) et des études pharmacocinétiques ont été réalisées avec des formulations sélectionnées. Des résultats positifs liés au masquage du goût amer pour les deux charges de PZQ (50 et 35 % en masse) ont pu être démontrés. Le troisième défi pour le PZQ à usage pédiatrique est le besoin d'un ajustement précis de la dose. Comme alternative pour surmonter le défi de l'ajustement des doses d'un médicament pédiatrique à base de PZQ pour les enfants, l'utilisation de la technologie d'impression 3D (FDM) avec alimentation directe de dispersions solides amorphes en poudre a été proposée. Nous avons pu démontrer la faisabilité d'obtenir des imprimés (printlets) avec deux doses différentes de PZQ (100 et 150 mg) en utilisant la technologie de FDM. Les printlets avec 35 % en masse de PZQ et SPAN 20 ont montré la meilleure performance de dissolution. Ce travail a démontré l'intérêt d’une dispersion solide amorphe ternaire contenant du PZQ sous forme de pellets ou de poudre pour l'impression 3D directe (FDM). Les principaux obstacles à la formulation du PZQ, tels qu'une faible solubilité du médicament, un goût inapproprié et des exigences de dosage élevées et variables, peuvent être surmontés en utilisant la combinaison de différents technologies (production d'ASD par HME et FDM comme technologie d'impression 3D).

Repaglinide is an oral blood-glucose-lowering drug used to manage type-2 diabetes mellitus by lowering post-prandial glucose by stimulating insulin secretion from pancreatic beta cells. According to the biopharmaceutical classification system, repaglinide falls under the class II category. For such drugs, limited solubility and poor dissolution rate are the major hurdles to overcome by formulation scientists, as they hinder drug absorption and lead to inadequate therapeutic effects. Therefore, this review aims to discuss in depth the various approaches investigated in the past five years to improve the solubility and dissolution of orally administered repaglinide: namely, solid dispersion, co-amorphous technology, cyclodextrin complexation, phospholipid complexes and polymeric micelles, nanocrystals, nanosuspensions and nanofibers.

The aim of this study is to evaluate the specific interactions, solid-state, and solution-state interactions between drug and polymers in amorphous spray dried dispersions and evaluate the subsequent impact on drug dissolution in non-sink media. This is intended to be used as a screening tool for dosage-form development. Formulations with specific theoretical and observed interactions between drug and polymer may exhibit improved dissolution rate, increased absorption rate, increased capacity for drug loading and improved physical stability. Four BCS II class drugs were evaluated: ibuprofen, ketoprofen, nifedipine, and itraconazole. Binary and ternary spray dried dispersions were manufactured with conventional polymers and arabinogalactan. Specific interaction parameters between each drug and polymer were determined using theoretical group contribution calculations and DSC data. Solid-state interactions were evaluated using modulated DSC and FTIR, and solution-state interactions were evaluated using 1H-NMR. The maximum amorphous content for each formulation was calculated from the enthalpy of melting point peaks using DSC. Flory-Huggins Specific Interaction Parameters were calculated and show that a negative specific parameter was associated with increased solid-state interactions and improved capacity to contain drug in the amorphous state. Correlations between Flory-Huggins specific interaction parameter, amorphous drug loading, and equilibrium solubility were established. Ternary spray-dried dispersions containing drug, conventional polymer, and arabinogalactan displayed similar hydrogen bonding as was observed with binary spray-dried dispersions. Solid and solution-state interactions observed in binary systems may be incorporated into ternary systems with arabinogalactan to both maintain amorphous drug capacity and improve dissolution rate compared to the binary. Supersaturation of amorphous binary and ternary dispersions was attained as compared to the crystalline drug. Mechanical properties of polymers as related to dissolution rate were investigated, and ternary systems containing to rapidly swelling and dissolving arabinogalactan had more pronounced erosion properties as compared to binary drug : HPMC dispersions. The resultant ternary systems are an improvement over binary drug polymer systems.

Clinical use of 4-Allylpyrocatechol (APC), a potential antifungal agent from Piper betle, is limited because of its low water solubility. The current study explores the development of the self-nanoemulsifying drug delivery system (SNEDDS) containing APC (APC-SNEDDS) to enhance APC solubility. Results demonstrated that excipient type and concentration played an important role in the solubility of APC in the obtained SNEEDS. SNEDDS, comprising 20% Miglyol 812N, 30% Maisine 35-1, 40% Kolliphor RH40, and 10% absolute ethanol, provided the highest loading capacity and significantly increased water solubility of APC. Oil-in-water nanoemulsions (NE) with droplet sizes of less than 40 nm and a narrow size distribution were obtained after dispersing this APC-SNEDDS in water. The droplets had a negative zeta potential between −10 and −20 mV. The release kinetics of APC from APC-SNEDDS followed the Higuchi model. The NE containing 1.6 mg APC/mL had effective activity against Candida albicans with dose-dependent killing kinetics and was nontoxic to normal cells. The antifungal potential was similar to that of 1 mg nystatin/mL. These findings suggest that APC-SNEDDS are a useful system to enhance the apparent water solubility of APC and are a promising system for clinical treatment of oral infection caused by C. albicans.

Fahad Mehmood Khan,1 Mahmood Ahmad,2 Hafiz Arfat Idrees1 1Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Punjab 63100, Pakistan; 2Faculty of Pharmacy, University of Central Punjab, Punjab 54000, PakistanCorrespondence: Mahmood Ahmad Tel +92 300 9682258Email ma786_786@yahoo.comPurpose: To enhance the solubility and dissolution profile of simvastatin (SIM) through co-crystallization with varying ratios of nicotinamide (NIC) using various co-methods.Materials and Methods: Twelve SIM:NIC co-crystal formulations (F01–F12) were prepared using dry grinding, slurry, liquid-assisted grinding, and solvent-evaporation methods, and their properties compared. Optimized formulations were selected on the basis of dissolution profiles and solubility for in vivo studies. The angle of repose, Carr Index and Hausner ratio were calculated to evaluate flow properties. Differential light scattering (DLS) was used to estimate particle-size distribution. Scanning electron microscopy (SEM) was employed to evaluate surface morphology. Thermal analyses and Fourier-transform infrared (FTIR) spectroscopy were used to determine the ranges of thermal stability and physical interaction of formulated co-crystals. X-ray powder diffraction (XPD) spectroscopy was used to determine the crystalline nature. Solubility and dissolution studies were undertaken to determine in vitro drug-release behaviors.Results: Micromeritic analyses revealed the good flow properties of formulated co-crystals. DLS showed the particle size of co-crystals to be in the nanometer range. SEM revealed that the co-crystals were regular cubes. Thermal studies showed the stability of co-crystals at > 300°C. FTIR spectroscopy revealed minor shifts of various peaks. XPD spectroscopy demonstrated co-crystal formation. The formulations exhibited an improved dissolution profile with marked improvements in solubility. In vivo studies showed a 2.4-fold increase in Cmax whereas total AUC(0–∞) was increased 4.75-fold as compared with that of SIM tablets.Conclusion: Co-crystallization with NIC improved the solubility and dissolution profile and, hence, the bioavailability of the poorly water-soluble drug SIM.Keywords: pharmacokinetics, solubility enhancement, simvastatin, nicotinamide, co-crystal

Poor aqueous solubility is currently a prevalent issue in the development of small molecule pharmaceuticals. Several methods are possible for improving the solubility, dissolution rate and bioavailability of Biopharmaceutics Classification System (BCS) class II and class IV drugs. Two solid state approaches, which rely on reductions in order, and can theoretically be applied to all molecules without any specific chemical prerequisites (compared with e.g. ionizable or co-former groups, or sufficient lipophilicity), are the use of the amorphous form and nanocrystals. Research involving these two approaches is relatively extensive and commercial products are now available based on these technologies. Nevertheless, their formulation remains more challenging than with conventional dosage forms. This article describes these two technologies from both theoretical and practical perspectives by briefly discussing the physicochemical backgrounds behind these approaches, as well as the resulting practical implications, both positive and negative. Case studies demonstrating the benefits and challenges of these two techniques are presented.

Our study aimed to develop an &ldquo, ex tempore&rdquo, reconstitutable, viscosity enhancer- and preservative-free meloxicam (MEL)-loaded polymeric micelle formulation, via Quality by Design (QbD) approach, exploiting the nose-to-brain pathway, as a suitable tool in the treatment of neuroinflammation. The anti-neuroinflammatory effect of nose-to-brain NSAID polymeric micelles was not studied previously, therefore its investigation is promising. Critical product parameters, encapsulation efficiency (89.4%), Z-average (101.22 &plusmn, 2.8 nm) and polydispersity index (0.149 &plusmn, 0.7) and zeta potential (&minus, 25.2 &plusmn, 0.4 mV) met the requirements of the intranasal drug delivery system (nanoDDS) and the targeted profile liquid formulation was transformed into a solid preservative-free product by freeze-drying. The viscosity (32.5 &plusmn, 0.28 mPas) and hypotonic osmolality (240 mOsmol/L) of the reconstituted formulation provides proper and enhanced absorption and probably guarantees the administration of the liquid dosage form (nasal drop and spray). The developed formulation resulted in more than 20 times faster MEL dissolution rate and five-fold higher nasal permeability compared to starting MEL. The prediction of IVIVC confirmed the great potential for in vivo brain distribution of MEL. The nose-to-brain delivery of NSAIDs such as MEL by means of nanoDDS as polymeric micelles offers an innovative opportunity to treat neuroinflammation more effectively.

Low solubility of active pharmaceutical compounds (APIs) remains an important challenge in dosage form development process. In the manuscript, empirical models were developed and analyzed in order to predict dissolution of bicalutamide (BCL) from solid dispersion with various carriers. BCL was chosen as an example of a poor water-soluble API. Two separate datasets were created: one from literature data and another based on in-house experimental data. Computational experiments were conducted using artificial intelligence tools based on machine learning (AI/ML) with a plethora of techniques including artificial neural networks, decision trees, rule-based systems, and evolutionary computations. The latter resulting in classical mathematical equations provided models characterized by the lowest prediction error. In-house data turned out to be more homogeneous, as well as formulations were more extensively characterized than literature-based data. Thus, in-house data resulted in better models than literature-based data set. Among the other covariates, the best model uses for prediction of BCL dissolution profile the transmittance from IR spectrum at 1260 cm−1 wavenumber. Ab initio modeling–based in silico simulations were conducted to reveal potential BCL–excipients interaction. All crucial variables were selected automatically by AI/ML tools and resulted in reasonably simple and yet predictive models suitable for application in Quality by Design (QbD) approaches. Presented data-driven model development using AI/ML could be useful in various problems in the field of pharmaceutical technology, resulting in both predictive and investigational tools revealing new knowledge.

This study aimed to enhance the solubility and release characteristics of docetaxel by synthesizing highly porous and stimuli responsive nanosponges, a nano-version of hydrogels with the additional qualities of both hydrogels and nano-systems. Nanosponges were prepared by the free radical polymerization technique and characterized by their solubilization efficiency, swelling studies, sol-gel studies, percentage entrapment efficiency, drug loading, FTIR, PXRD, TGA, DSC, SEM, zeta sizer and in vitro dissolution studies. In vivo toxicity study was conducted to assess the safety of the oral administration of prepared nanosponges. FTIR, TGA and DSC studies confirmed the successful grafting of components into the stable nano-polymeric network. A porous and sponge-like structure was visualized through SEM images. The particle size of the optimized formulation was observed in the range of 195 ± 3 nm. The fabricated nanosponges noticeably enhanced the drug loading and solubilization efficiency of docetaxel in aqueous media. The drug release of fabricated nanosponges was significantly higher at pH 6.8 as compared to pH 1.2 and 4.5. An acute oral toxicity study endorsed the safety of the system. Due to an efficient preparation technique, as well as its enhanced solubility, excellent physicochemical properties, improved dissolution and non-toxic nature, nanosponges could be an efficient and a promising approach for the oral delivery of poorly soluble drugs.

Poor drug solubility represents a major problem for the development of new drug delivery systems. Finding new excipients that promote drug solubility is one of the strategies currently used. In this context, ionic liquids (ILs) have been studied as solubility promoters due to their ability to be placed in either lipophilic or hydrophilic solutions. Two choline-based ILs, [Cho][Met] and [Cho][Cys], were prepared and their influence on the solubility of a model hydrophilic drug, caffeine, was evaluated at 25 ºC. Results show that both ILs improved drug solubility, with [Cho][Met] providing a higher soluble concentration. Our results suggest that the studied choline-based ILs are effective solubility enhancers of caffeine and thus may potentially be used as functional ingredients in drug delivery systems.

Muhammad Farhan Sohail,1–3 Mubashar Rehman,4,5 Hafiz Shoaib Sarwar,2 Sara Naveed,1 Omer Salman,6 Nadeem Irfan Bukhari,7 Irshad Hussain,3 Thomas J Webster,5 Gul Shahnaz21Riphah Institute of Pharmaceutical Sciences, Riphah International University, Lahore Campus, Lahore, 2Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 3Department of Chemistry, SBA School of Science and Engineering (SBASSE), Lahore University of Management Sciences (LUMS), Lahore, 4Department of Pharmacy, University of Lahore-Gujrat Campus, Gujrat, 5Department of Chemical Engineering, Northeastern University, Boston, MA, USA; 6Department of Pharmacy, University of Lahore, Lahore Campus, 7University College of Pharmacy, University of the Punjab, Allama Iqbal Campus, Lahore, Pakistan Abstract: The oral delivery of cancer chemotherapeutic drugs is challenging due to low bioavailability, gastrointestinal side effects, first-pass metabolism and P-glycoprotein efflux pumps. Thus, chemotherapeutic drugs, including Docetaxel, are administered via an intravenous route, which poses many disadvantages of its own. Recent advances in pharmaceutical research have focused on designing new and efficient drug delivery systems for site-specific targeting, thus leading to improved bioavailability and pharmacokinetics. A decent number of studies have been reported for the safe and effective oral delivery of Docetaxel. These nanocarriers, including liposomes, polymeric nanoparticles, metallic nanoparticles, hybrid nanoparticles, dendrimers and so on, have shown promising results in research papers and clinical trials. The present article comprehensively reviews the research efforts made so far in designing various advancements in the oral delivery of Docetaxel. Different strategies to improve oral bioavailability, prevent first-pass metabolism and inhibition of efflux pumping leading to improved pharmacokinetics and anticancer activity are discussed. The final portion of this review article presents key issues such as safety of nanomaterials, regulatory approval and future trends in nanomedicine research. Keywords: anticancer, permeability enhancement, solubility enhancement, P-glycoproteins, efflux pump, first-pass metabolism

The aim of this study was to enhance aqueous solubility of xanthone with natural polymers using oil-in-water emulsion and complex coacervation as the microencapsulation techniques. There was no interaction between xanthone and the wall material; and xanthone crystallinity was decreased as observed via fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and x-ray powder diffraction (XRD) after microencapsulation. Oil-in-water emulsion and coacervation increased xanthone solubility by 37-fold and 1.6-fold, respectively. However, O/W emulsion method required a high ratio of oil to xanthone. The solubilizing effect of oil and wall material, particle size reduction, and decreased crystallinity were responsible for enhancing the aqueous solubility of xanthone.

Ursodeoxycholic acid (UDCA) is considered the first-choice therapy for cholestatic disorders. To enhance solubility and exploit specific transporters in liver, we synthesized a new galactosyl pro-drug of UDCA (UDCAgal). Ethinylestradiol (EE)-induced cholestasis was used to study and compare the effects of UDCAgal with UDCA on bile flow, hepatic canalicular efflux transporter expression, and inflammation. UDCAgal resulted quite stable both at pH 7.4 and 1.2 and regenerated the parent drug after incubation in human plasma. Its solubility, higher than UDCA, was pH- and temperature-independent. UDCAgal displayed a higher cell permeation compared to UDCA in liver HepG2 cells. Moreover, in cholestatic rats, UDCAgal showed a higher potency compared to UDCA in reducing serum biomarkers (AST, ALT, and ALP) and cytokines (TNF-α and IL-1β). The higher effect of UDCAgal on the increase in bile salt export pump and multidrug resistance-associated protein 2 transcription indicated an improved spillover of bile acids from the liver. UDCAgal showed a reduction in CCL2, as well as TNF-α, IL-1β, and cyclooxygeanse-2 mRNAs, indicating a reduction in hepatic neutrophil accumulation and inflammation. Moreover, UDCAgal, similarly to UDCA, heightens bile flow and modulates biliary acids secretion. These results indicate that UDCAgal has a potential in the treatment of cholestatic disease.

Aprepitant (APR) belongs to Class II of the Biopharmaceutical Classification System (BCS) because of its low aqueous solubility. The objective of the current work is to develop self-nanoemulsifying drug delivery systems (SNEDDS) of APR to enhance its aqueous solubility. Preformulation studies involving screening of excipients for solubility and emulsification efficiency were carried out. Pseudo ternary phase diagrams were constructed with blends of oil (Imwitor® 988), cosolvent (Transcutol® P), and various surfactants (Kolliphor® RH40, Kolliphor® ELP, Kolliphor® HS15). The prepared SNEDDS were characterized for droplet size and nanoemulsion stability after dilution. Supersaturated SNEDDS (super-SNEDDS) were prepared to increase the quantity of loaded APR into the formulations. HPMC, PVP, PVP/VA, and Soluplus® were used as polymeric precipitation inhibitors (PPI). PPIs were added to the formulations at 5% and 10% by weight. The influence of the PPIs on drug precipitation was investigated. In vitro lipolysis test was carried out to simulate digestion of formulations in the gastrointestinal tract. Optimized super-SNEDDS were formulated into free-flowing granules by adsorption on the porous carriers such as Neusilin® US2. In vitro dissolution studies of solid super-SNEDDS formulation revealed an increased dissolution rate of the drug due to enhanced solubility. Consequently, a formulation to improve the solubility and potentially bioavailability of the drug was developed.

Baicalin is a flavone glycoside extracted from Scutellaria baicalensis, a traditional Chinese herbal medicine. Numerous pharmacological effects of baicalin were reported (e.g. antioxidant, anxiolytic); nevertheless, the most important physicochemical properties influencing the pharmacokinetic behaviour and the concomitant oral bioavailability have not yet been described in a comprehensive study. The aim of this project was to characterize the acid-base, lipophilicity, biorelevant solubility and permeability properties of the drug substance and providing scientific data to support the dosage form design. Another important objective was the comparative evaluation of six various baicalin-cyclodextrin (CD) inclusion complexes along with the creation of a suitable Drug Delivery System (DDS) for this BCS IV drug. Biorelevant profiling was carried out by NMR-pH titrations, saturation shake-flask and distribution coefficients (logP) measurements, while CD inclusion studies were fulfilled by experimental methods (phase solubility, 1H/13C NMR, 2D ROESY) and computational approaches. Due to low aqueous solubility (67.03 ± 1.60 μg/ml) and low permeability (Papp = 0.037 × 10−6 cm/s), baicalin is classified as BCS IV. The γ-CD complexation significantly increased the solubility of baicalin (~ 5 times). The most promoted chemical shift change occurred in baicalin-γ-CD complex. Computational studies showed disparate binding pattern for baicalin in case of β- and γ-CD; furthermore, the calculated complexation energy was − 162.4 kJ mol−1 for β-CD, while it was significantly stronger for γ-CD (− 181.5 kJ mol−1). The physicochemical and structural information of baicalin and its CD complexes introduced herein can create molecular basis for a promising DDS with enhanced bioavailability containing a bioactive phytopharmacon.

The recent innovative advance in nanotechnology has led to the development of targeted drug delivery system. Targeting a molecule to a particular site with the help of a drug delivery system efficiently requires the use of specialized drug delivery systems. The invention of Nano sponges has become a significant step in overcoming the problems associated with conventional drug delivery systems. These are able to carry both hydrophilic and hydrophobic drugs. Nano sponge technology widely provide the controlled and predictable release of the drug to the targeted site. The Nano sponge particles circulate around the body and get attached with the target site and release the drug. A wide variety of drugs can be incorporated in the Nano sponge formulation since it possess a porous structure in nature. Nano sponge technology has been studied widely for the drug delivery by oral administration, topical administration and parenteral administration. Nano sponges can be used to prevent drug and protein degradation. Another important characteristic of Nano sponge is that they can improve the solubility of poorly water soluble drug. In this review advantages, composition, method of preparation, evaluation and application of different formulations of drugs and recent studies on Nano sponge have been discussed.

Among the many methods available for solubility enhancement, mesoporous carriers are generating significant industrial interest. Owing to the spatial confinement of drug molecules within the mesopore network, low solubility crystalline drugs can be converted into their amorphous counterparts, which exhibit higher solubility. This work aims to understand the impact of drug overloading, i.e., above theoretical monolayer surface coverage, within mesoporous silica on the release behaviour and the thermal properties of loaded drugs. The study also looks at the inclusion of hypromellose acetate succinate (HPMCAS) to improve amorphisation. Various techniques including DSC, TGA, SEM, assay and dissolution were employed to investigate critical formulation factors of drug-loaded mesoporous silica prepared at drug loads of 100&ndash, 300% of monolayer surface coverage, i.e., monolayer, double layer and triple layer coverage. A significant improvement in the dissolution of both Felodipine and Furosemide was obtained (96.4% and 96.2%, respectively). However, incomplete drug release was also observed at low drug load in both drugs, possibly due to a reversible adsorption to mesoporous silica. The addition of a polymeric precipitation inhibitor HPMCAS to mesoporous silica did not promote amorphisation. In fact, a partial coating of HPMCAS was observed on the exterior surface of mesoporous silica particles, which resulted in slower release for both drugs.

Background and Objectives: Lipid-based self-nanoemulsifying drug delivery systems (SNEDDS) have resurged the eminence of nanoemulsions by modest adjustments and offer many valuable opportunities in drug delivery. Chlorpromazine, an antipsychotic agent with poor aqueous solubility&mdash, with extensive first-pass metabolism&mdash, can be a suitable candidate for the development of SNEDDS. The current study was designed to develop triglyceride-based SNEDDS of chlorpromazine to achieve improved solubility, stability, and oral bioavailability. Materials and Methods: Fifteen SNEDDS formulations of each short, medium, and long chain, triglycerides were synthesized and characterized to achieve optimized formulation. The optimized formulation was characterized for several in vitro and in vivo parameters. Results: Particle size, zeta potential, and drug loading of the optimized SNEDDS (LCT14) were found to be 178 &plusmn, 16, &minus, 21.4, and 85.5%, respectively. Long chain triglyceride (LCT14) showed a 1.5-fold increased elimination half-life (p &lt, 0.01), up to 6-fold increased oral bioavailability, and 1.7-fold decreased plasma clearance rate (p &lt, 0.01) compared to a drug suspension. Conclusion: The findings suggest that SNEDDS based on long-chain triglycerides (LCT14) formulations seem to be a promising alternative for improving the oral bioavailability of chlorpromazine.

The purpose of this paper is to examine the physical stability as well as viscoelastic properties of the binary amorphous ezetimibe&ndash, simvastatin system. According to our knowledge, this is the first time that such an amorphous composition is prepared and investigated. The tendency toward re-crystallization of the amorphous ezetimibe&ndash, simvastatin system, at both standard storage and elevated temperature conditions, have been studied by means of X-ray diffraction (XRD). Our investigations have revealed that simvastatin remarkably improves the physical stability of ezetimibe, despite the fact that it works as a plasticizer. Pure amorphous ezetimibe, when stored at room temperature, begins to re-crystallize after 14 days after amorphization. On the other hand, the ezetimibe-simvastatin binary mixture (at the same storage conditions) is physically stable for at least 1 year. However, the devitrification of the binary amorphous composition was observed at elevated temperature conditions (T = 373 K). Therefore, we used a third compound to hinder the re-crystallization. Finally, both the physical stability as well as viscoelastic properties of the ternary systems containing different concentrations of the latter component have been thoroughly investigated.

The crystal changes and salt formation of poorly water-soluble telmisartan (TEL) in various solvents were investigated for enhanced solubility, stability and crystallinity. Polymorphic behaviors of TEL were characterized by dispersing in distilled water, acetone, acetonitrile, DMSO, or ethanol using Method I: without heat and then dried under vacuum at room temperature, and Method II: with heat below boiling temperature, cooled at 5 &deg, C, and then dried under vacuum at 40 &deg, C. For salt formation (Method III), the following four powdered mixtures were prepared by dispersing in solution of hydrochloric acid (HCl) (pH 1.2), TEL/HCl, in simulated gastric fluid (pH 1.2 buffer), TEL/simulated gastric fluid (SGF), in intestinal fluid (pH 6.8 buffer), TEL/simulated intestinal fluid (SIF), or in NaOH (pH 6.8), TEL/NaOH, respectively, and then dried under a vacuum at room temperature. The structures of powdered mixtures were then studied using a field emission scanning electron microscope (FESEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), FTIR, 1H nuclear magnetic resonance (1H-NMR), and LC&ndash, MS. The solubility of TEL in powdered forms was performed in pH 6.8, pH 1.2, and distilled water. No polymorphic behaviors of TEL were observed in various solvents as characterized by FESEM, DSC, PXRD, and FTIR. However, the structural changes of powdered mixtures obtained from Method III were observed due to the formation of salt form. Moreover, the solubility of salt form (TEL/HCl) was highly increased as compared with pure TEL. There were no significant changes of TEL/HCl compared with TEL in the content assay, PXRD, DSC, and FTIR during stressed storage conditions at 40 &deg, C/75% relative humidity (RH) for 4 weeks under the closed package condition. Therefore, the present study suggests the new approach for the enhanced stability and solubility of a poorly water-soluble drug via salt form.

smartPearls are a dermal delivery system for poorly soluble active agents, consisting of nanoporous silica particles loaded with a long-term stable, amorphous active agent in its mesopores (2–50 nm). The amorphous state of the active agent is known to increase dermal bioavailability. For use in marketed products, optimal silica types were identified from commercially available, regulatory accepted silica. In addition, a scalable production process was demonstrated. The loading of the particles was performed by applying the immersion–evaporation method. The antioxidant rutin was used as a model active agent and ethanol was applied as the solvent. Various silica particles (Syloid®, Davisil®) differing in particle size (7–50 µm), pore diameter (3–25 nm) and pore volume (0.4–1.75 mL/g) were investigated regarding their ease of processing. The evaporation from the silica–ethanol suspensions was performed in a rotary evaporator. The finest powders were obtained with larger-sized silica. The maximum loading staying amorphous was achieved between 10% and 25% (w/w), depending on the silica type. A loading mechanism was also proposed. The most suitable processing occurred with the large-sized Syloid® XDP 3050 silica with a 50 µm particle size and a pore diameter of 25 nm, resulting in 18% (w/w) maximum loading. Based on a 10% (w/w) loading and the amorphous solubility of the active agent, for a 100 kg dermal formulation, about 500 g of loaded particles were required. This corresponds to production of 5 kg of loaded smartPearls for a formulation batch size of a ton. The production of 5 kg (i.e., about 25 L of solvent removal) can be industrially realized in a commercial 50 L rotary evaporator.

Resveratrol and oxyresveratrol are natural polyphenolic stilbenes with several important pharmacological activities. However, low solubility and aqueous instability are the major limitations in their drug delivery applications. In the present work, we demonstrated the encapsulation of resveratrol and oxyresveratrol with nanosponge to improve solubility and stability. Several characterization techniques were used to confirm the encapsulation of both drug molecules within the nanosponges. The high encapsulation efficiency of resveratrol (77.73%) and oxyresveratrol (80.33%) was achieved within the nanosponges. Transmission electron microscopy suggested uniform spherical size particles of resveratrol and oxyresveratrol loaded nanosponges. Compared to free drugs, better protection against UV degradation was observed for resveratrol-loaded nanosponge (2-fold) and oxyresveratrol-loaded nanosponge (3-fold). Moreover, a higher solubilization of resveratrol- and oxyresveratrol-loaded nanosponges lead to a better antioxidant activity compared to drug molecules alone. Cytotoxicity studies against DU-145 prostate cancer cell lines further suggested improved activity of both resveratrol and oxyresveratrol-loaded nanosponges without any significant toxicity of blank nanosponges.

Kynurenic acid demonstrates antioxidant, neuroprotective and free radical scavenging properties. However, low aqueous solubility of kynurenic acid limits its therapeutic activity. In the present study, cyclodextrin nanosponges were used to improve the solubility and therapeutic activity of kynurenic acid. The formation of kynurenic acid loaded nanosponge was confirmed by different characterization techniques. The solubility of kynurenic acid was significantly increased with nanosponge (111.1 μg/ml) compared to free kynurenic acid (16.4 μg/ml) and β-cyclodextrin (28.6 μg/ml). High drug loading (19.06%) and encapsulation efficiency (95.31%) were achieved with NS. The particle size and zeta potential of kynurenic acid loaded nanosponge was around 255.8 nm and −23 mV respectively. Moreover, higher solubilization of kynurenic acid loaded nanosponge produced better antioxidant activity compared to free kynurenic acid. The kynurenic acid loaded nanosponge and blank nanosponge were found nontoxic in the cytotoxicity assay. Thus, these studies demonstrated that nanosponges can be used as a carrier for the delivery of kynurenic acid.