Reversed-phase-HPLC enantioseparation and control of enantiomeric purity of duloxetine using a new chiral reagent and recovery of enantiomers.

This study reports a rapid and low-cost LC method for control of enantiomeric purity of duloxetine. Though duloxetine, as marketed and administered, is expected to be a single (S)-enantiomer, the analysis of a few commercial branded samples by the method developed and presented here showed that they contain a relatively high percentage of (R)-enantiomer (e.g., 2.71-5.42%, which is undesirable in drug formulations). A new chiral derivatizing reagent [isatinyl-(S)-naproxen amide] was synthesized on (S)-naproxen platform. Diastereomeric derivatives were synthesized under microwave irradiation and were separated using reversed-phase-HPLC on a C18 column. A combination of acetonitrile and triethylammonium phosphate buffer (9 mM, pH 4) as the mobile phase and detection at 273 nm were found successful. The diastereomeric derivatives at preparative scale were separated using open column chromatography, and the native enantiomers were obtained and characterized. The HPLC separation method was validated for detection limit, linearity, accuracy, and precision. The limits of detection of (S,R)-diastereomer and (S,S)-diastereomer were found to be 12 and 16 pg/mL, respectively, for the 20-µL injected volume. The method so developed has a practical significance and greater societal impact in establishing the control of enantiomeric purity and in ensuring the enantiomeric purity of the drug meant for human consumption.

Achiral and chiral analysis of duloxetine by chromatographic and electrophoretic methods, a review on the separation methodologies.

Duloxetine (DLX) is a widely used antidepressant drug belonging to the class of selective serotonin and norepinephrine reuptake inhibitors (SNRIs); its efficacy has been demonstrated in the treatment of not only major depressive disorders but also diabetic neuropathic pain, generalized anxiety disorder, fibromyalgia or stress urinary incontinence. It is a chiral substance and is used in therapy in the form of the enantiopure S-DLX, which is twice as active as R-DLX. Several methods have been published for the achiral and chiral determination of DLX in pharmaceuticals, biological materials and environmental samples, the majority using liquid chromatography and capillary electrophoresis coupled with different detection techniques (UV detection, fluorescence, mass spectrometry). The aim of the current review is to provide a systematic survey of the analytical techniques used for the determination of DLX from different matrices.

Polymer-based prolonged-release nanoformulation of duloxetine: fabrication, characterization and neuropharmacological assessments.

OBJECTIVE: The poly D, L-Lactic-co-glycolic acid (PLGA) and Polycaprolactone (PCL) have been widely applied for developing the prolonged-release formulation. The current study explores the application of these polymers for developing prolonged-release nanosphere of Duloxetine (DLX). Developing a prolonged release parenteral nanosphere formulation of DLX would be overcoming pitfalls like acid-labile degradation, first-pass metabolism and erratic bioavailability along with long-term therapeutic benefit in the treatment of depression. METHODS: DLX-loaded PLGA and PCL nanospheres were prepared by using the emulsion solvent evaporation technique. The developed formulation was compared with DLX oral solution concerning brain estimation. The prepared nanospheres were subjected to the morphology of the drug particles, polydispersity Index (PDI), distribution size, zeta potential, entrapment efficiency and percentage yield to generate a proof of concept. RESULTS: DLX-loaded polymeric nanosphere exhibited the uniform size from 89.48 nm to 100.9 nm. The entrapment efficiency was in the range of 74.93 to 77.49, respectively, of PLGA and PCL formulation. The FSEM image affirmed smooth spherical morphology. A good PDI and negative zeta potential value (-31.3 mV for F1 and -30.7 mV for F2) supported the stability of the nanosphere. The brain concentration of the drug was three times enhanced supporting the effectiveness of the nanosphere during pharmacodynamic and pharmacokinetic studies. CONCLUSION: The intramuscular DLX-loaded nanospheres signify improved brain availability relative to DLX solution. This can be a blueprint for the effective and targeted brain delivery of CNS drugs.

Brain Targeting of Duloxetine HCL via Intranasal Delivery of Loaded Cubosomal Gel: In vitro Characterization, ex vivo Permeation, and in vivo Biodistribution Studies.

PURPOSE: Duloxetine (DLX) is dual serotonin and norepinephrine reuptake inhibitor suffering from limited bioavailability (≈ 40%) due to extensive hepatic metabolism. This work aims to formulate and evaluate DLX intranasal thermoreversible cubosomal gels to enhance its bioavailability and ensure efficient brain targeting. MATERIALS AND METHODS: Cubo-gels were prepared by 33 central composite design with three independent factors, lipid ratio (glycerol monooleate: glycerol tripalmitate), Pluronic F127%, and Pluronic F68%. The prepared formulations were evaluated for their particle size (PS), gelling temperature (GT), entrapment efficiency (EE%), and in vitro release. The cubo-gel with the highest desirability (0.88) was chosen as the optimized formulation. DLX cubo-gel was evaluated using differential scanning calorimetry, Fourier-transform infrared spectroscopy, X-ray powder diffraction, and transmission electron microscopy. Cytotoxicity study, ex vivo permeation study and in vivo bio-distribution study were conducted to evaluate the safety and efficacy of brain targeting. RESULTS: The optimum cubo-gel was composed of 3.76 lipid ratio, 20% w/v PF127, and 5% w/v PF68. It had PS of 265.13 ± 9.85 nm, GT of 32 ± 0.05°C, EE% of 98.13 ± 0.50%, and showed controlled release behavior where 33% DLX was released within 6 hrs. The plain in situ cubo-gel had a significantly higher IC50 compared to DLX solution and DLX-loaded in situ cubo-gel. The ex vivo permeation study showed 1.27 enhancement in the drug permeation from DLX in situ cubo-gel. According to the in vivo bio-distribution study in plasma and brain, the intranasal DLX in situ cubo-gel showed a 1.96 fold improvement in brain bioavailability compared to the intranasal solution. Its BTE% and DTP% were 137.77 and 10.5, respectively, indicating efficient brain targeting after intranasal administration. CONCLUSION: Accordingly, intranasal DLX in situ cubo-gel can be considered as an innovative nano-carrier delivery system for bioavailability enhancement and efficient brain targeting of DLX to maximize its effect.

Impact of cyclodextrin derivatives on systemic release of duloxetine HCl via buccal route.

Aim: The aim of this work was to develop buccoadhesive tablets for the systemic delivery of duloxetine HCl (DXT) using more soluble derivatives of ß-cyclodextrin, i.e. hydroxypropyl-ß-cyclodextrin (HPßCD) and sulfobutylether-ß-cyclodextrin (SBEßCD) and to investigate enhanced cellular uptake of inclusion complexed drug.Materials and methods: Freeze dried and spray dried complexes of both cyclodextrin derivatives with DXT (1:1 molar) were prepared and characterized with DSC, FTIR, and PXRD techniques. C971 and PC, on the basis of swelling behavior, erosion and in vitro residence time, were selected for further study at different levels (-1, 0, +1) to optimize the formulation in terms of enhanced drug release and ex vivo permeation.Results: SBEßCD based complexes show more aqueous solubility of DXT (0.782 and 0.958 mM) and more complexation efficiency compared to HPßCD at 25 °C and 37 °C, respectively. Apparent stability constant was reported to be higher (1109.94 and 1693.25 M-1) for DXT-SBEßCD at 25 °C and 37 °C, respectively, than the corresponding values for DXT-HPßCD systems. Enhanced cellular uptake using fibroblast cells was revealed for complexed drug compared to free drug .Conclusion: Both cyclodextrin derivatives are able to enhance drug release and permeation in vitro and ex vivo.

Preclinical evidence of enhanced analgesic activity of duloxetine complexed with succinyl-ß-cyclodextrin: A comparative study with cyclodextrin complexes.

Chronic pain represents one of the most important public health problems, with a great prevalence of comorbidity with depression and cognitive decline. Antidepressants such as duloxetine, a serotonin-norepinephrine reuptake inhibitor, represent an essential part of the therapeutic strategy for chronic pain management in addition to classical analgesics. Duloxetine is endowed with good efficacy and a good profile of safety and tolerability. Yet, duloxetine is metabolized by the cytochrome P450 system 2D6 and 1A2 (CYP2D6 and CYP1A2) and it exhibits moderate inhibitory activity on CYP2D6, resulting in side effects and metabolic interactions that may occur on a long term therapeutic schedule. Cyclodextrins (CyDs) are used in pharmaceutical applications for numerous purposes, including the improvement of drug bioavailability. In order to evaluate their effects on the activity of duloxetine, we first spectrophotometrically studied the host-guest complexes obtained combining duloxetine and different ß-CyD derivatives (ß-CyD, ß-CyDen-c-(Glu-Glu), and succinyl-ß-CyD) and then performed in vivo and in vitro studies. Among duloxetine/CyDs complexes, succinyl-ß-CyD ameliorated the analgesic activity of duloxetine in the tail flick test and in the formalin test in mice and significantly protected the drug from CYP2D6 metabolism.

Degradation of duloxetine: Identification of transformation products by UHPLC-ESI(+)-HRMS/MS, in silico toxicity and wastewater analysis.

Duloxetine (DUL), an antidepressant drug, has been detected in surface water and wastewater effluents, however, there is little information on the formation of its transformation products (TPs). In this work, hydrolysis, photodegradation (UV irradiation) and chlorination experiments were performed on spiked distillated water, under controlled experimental conditions to simulate abiotic processes that can occur in the environment and wastewater treatment plants (WWTPs). Eleven TPs, nine from reaction with UV light and two from chlorine contact, were formed and detected by ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry, and nine of them had their chemical structures elucidated upon analyses of their fragmentation patterns in MS/MS spectra. The formation and degradation of the TPs were observed. The parent compound was completely degraded after 30 min in photodegradation and after 24 hr in chlorination. Almost all TPs were completely degraded in the experiments. The ecotoxicity and mutagenicity of the TPs were predicted based on several in silico models and it was found that a few of these products presented more ecotoxicity than DUL itself and six TPs showed positive mutagenicity. Finally, wastewater samples were analyzed and DUL and one TP, possibly formed by chlorination process, were detected in the effluent, which showed that WWTP not only did not remove DUL, but also formed a TP.

A three-pronged formulation approach to improve oral bioavailability and therapeutic efficacy of two lipophilic drugs with gastric lability.

The aim of present study was to co-administer curcumin (CRM) liquisolid pellets and coated duloxetine hydrochloride (DXH) pellets in rats to treat neuropathic pain (NP) associated with chronic constriction injury (CCI). To formulate liquisolid pellets of CRM, it was first dissolved in Tween-80 and then adsorbed on the porous surface of MCC PH102 and Syloid XDP that were used as carrier and coating materials, respectively. Central composite design was used to optimize the liquisolid formulation. The results of powder X-ray diffraction studies, differential scanning calorimetry, and scanning electron microscopy showed complete solubility of drug in Tween-80 followed by its complete adsorption on the porous surface of Syloid XDP and MCC PH102. Both DXH and liquisolid CRM powders were converted into pellets using extrusion-spheronization. DXH pellets were further coated with Eudragit S100 to bypass the gastric pH. About 32.31-fold increase in dissolution rate of CRM present in liquisolid formulation was observed as compared to its unprocessed form. Similarly, the dissolution profile in 0.1 N HCl for Eudragit S100-coated DXH showed complete protection of drug for 2 h and complete release after its introduction in buffer medium (0.2 M phosphate buffer pH 6.8). he pharmacokinetic studies carried out on rats revealed 7.3-fold increase in bioavailability of CRM present in liquisolid pellets and 4.1-fold increase in bioavailability of DXH present in coated pellets was observed as compared to their unprocessed pellets. This increase in bioavailability of drugs caused significant amelioration of CCI-induced pain in rats as compared to their unprocessed forms. The histological sections showed better improvement in regeneration of nerve fibers in rats.

Serotonin and Norepinephrine Reuptake Inhibitors.

This chapter covers antidepressants that fall into the class of serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors. That is, they bind to the 5-HT and NE transporters with varying levels of potency and binding affinity ratios. Unlike the selective serotonin (5-HT) reuptake inhibitors (SSRIs), most of these antidepressants have an ascending rather than a flat dose-response curve. The chapter provides a brief review of the chemistry, pharmacology, metabolism, safety and adverse effects, clinical use, and therapeutic indications of each antidepressant. Venlafaxine, a phenylethylamine, is a relatively weak 5-HT and weaker NE uptake inhibitor with a 30-fold difference in binding of the two transporters. Therefore, the drug has a clear dose progression, with low doses predominantly binding to the 5-HT transporter and more binding of the NE transporter as the dose ascends. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine (ODV; desvenlafaxine) by CYP2D6, and it therefore is subject to significant inter-individual variation in blood levels and response dependent on variations in CYP2D6 metabolism. The half-life of venlafaxine is short at about 5 h, with the ODV metabolite being 12 h. Both parent compound and metabolite have low protein binding and neither inhibit CYP enzymes. Therefore, both venlafaxine and desvenlafaxine are potential options if drug-drug interactions are a concern, although venlafaxine may be subject to drug-drug interactions with CYP2D6 inhibitors. At low doses, the adverse effect profile is similar to an SSRI with nausea, diarrhea, fatigue or somnolence, and sexual side effects, while venlafaxine at higher doses can produce mild increases in blood pressure, diaphoresis, tachycardia, tremors, and anxiety. A disadvantage of venlafaxine relative to the SSRIs is the potential for dose-dependent blood pressure elevation, most likely due to the NE reuptake inhibition caused by higher doses; however, this adverse effect is infrequently observed at doses below 225 mg per day. Venlafaxine also has a number of potential advantages over the SSRIs, including an ascending dose-antidepressant response curve, with possibly greater overall efficacy at higher doses. Venlafaxine is approved for MDD as well as generalized anxiety disorder, social anxiety disorder, and panic disorder. Desvenlafaxine is the primary metabolite of venlafaxine, and it is also a relatively low-potency 5-HT and NE uptake inhibitor. Like venlafaxine it has a favorable drug-drug interaction profile. It is subject to CYP3A4 metabolism, and it is therefore vulnerable to enzyme inhibition or induction. However, the primary metabolic pathway is direct conjugation. It is approved in the narrow dose range of 50-100 mg per day. Duloxetine is a more potent 5-HT and NE reuptake inhibitor with a more balanced profile of binding at about 10:1 for 5HT and NE transporter binding. It is also a moderate inhibitor of CYP2D6, so that modest dose reductions and careful monitoring will be needed when prescribing duloxetine in combination with drugs that are preferentially metabolized by CYP2D6. The most common side effects identified in clinical trials are nausea, dry mouth, dizziness, constipation, insomnia, asthenia, and hypertension, consistent with its mechanisms of action. Clinical trials to date have demonstrated rates of response and remission in patients with major depression that are comparable to other marketed antidepressants reviewed in this book. In addition to approval for MDD, duloxetine is approved for diabetic peripheral neuropathic pain, fibromyalgia, and musculoskeletal pain. Milnacipran is marketed as an antidepressant in some countries, but not in the USA. It is approved in the USA and some other countries as a treatment for fibromyalgia. It has few pharmacokinetic and pharmacodynamic interactions with other drugs. Milnacipran has a half-life of about 10 h and therefore needs to be administered twice per day. It is metabolized by CYP3A4, but the major pathway for clearance is direct conjugation and renal elimination. As with other drugs in this class, dysuria is a common, troublesome, and dose-dependent adverse effect (occurring in up to 7% of patients). High-dose milnacipran has been reported to cause blood pressure and pulse elevations. Levomilnacipran is the levorotary enantiomer of milnacipran, and it is pharmacologically very similar to the racemic compound, although the side effects may be milder within the approved dosing range. As with other NE uptake inhibitors, it may increase blood pressure and pulse, although it appears to do so less than some other medications. All medications in the class can cause serotonin syndrome when combined with MAOIs.

Investigation of dextrin-based synergistic system with chiral ionic liquids as additives for enantiomeric separation in capillary electrophoresis.

In this paper, two spiral structure CILs, 1-butyl-3-methylimidazolium(T-4)-bis[(2S)-2-(hydroxy-κO)-3-methyl-butanoato-κO]borate(BMIm+BLHvB-) and 1-butyl-3-methylimidazolium (T-4)-bis[(αS)-α-(hydroxy-κO)-4-methyl-benzeneacetato-κO]borate (BMIm+BSMB-)were applied to evaluate their potential synergistic effect with dextrin for CE enantiomeric separation. The established dextrin-based synergistic system with CILs as additives showed good separation performance towards four tested drugs, including duloxetine, ketoconazole, sulconazole and citalopram. It was also observed that significantly improved separation and selectivity for tested analytes were achieved in CILs/dextrin synergistic system compared to single dextrin system. Primary parameters, such as the concentration of CIL, dextrin concentration, buffer pH and applied voltage, were systematically investigated to optimize the enantiomeric separation with BMIm+BLHvB-/dextrin as model system. Finally, the method of Statistical Product and Service Solutions (SPSS) was exploited to further elucidate the influence of experimental parameters on the synergistic effect.

Duloxetine loaded-microemulsion system to improve behavioral activities by upregulating serotonin and norepinephrine in brain for the treatment of depression.

Duloxetine is a well-known antidepressant molecule which is used in the treatment of depression but due to poor solubility it suffers with the drawback of low oral bioavailability. The objective of present work was to formulate and characterize duloxetine loaded microemulsion to enhance the oral bioavailability. Prepared microemulsion was studied for droplet size, zeta potential, refractive index, polydispersity index (PDI), percentage transmittance, viscosity and in vitro release study. Optimized microemulsion (D1) showed spherical droplets with mean diameter of 35.40 ±â€¯3.11 nm, PDI of 0.170 and zeta potential values of -25.8 mV. Formulation showed good transmittance (greater than 99%), viscosity (0.205 Pa s) and refractive index (1.43 ±â€¯0.01). Increased duloxetine release was obtained with microemulsion in comparison to drug suspension. Behavioral tests like mobility test, tail suspension test and forced swimming test performed in depressed and treated rats with duloxetine microemulsion significantly improved the behavioral activities in comparison to duloxetine suspension. Pharmacokinetic studies showed that microemulsion exhibited 1.8 times increment in bioavailability in comparison to duloxetine suspension.

Formulation and optimization of duloxetine hydrochloride buccal films: in vitro and in vivo evaluation.

Duloxetine hydrochloride (DH) is a serotonin-norepinephrine reuptake inhibitor (SSNRI) indicated for the treatment of depression. Duloxetine suffers from reduced oral bioavailability (≈50%) due to hepatic metabolism. This study aims to develop DH buccoadhesive films to improve its bioavailability. DH buccoadhesive films were prepared adopting the solvent casting method using hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA). The prepared films were evaluated for weight uniformity, drug content, surface pH, swelling index, mucoadhesion strength and drug release percentages. Accelerated stability and bioavailability studies in healthy human volunteers were also performed for the selected films. Results of the evaluation tests showed that the optimum physicochemical characters were obtained by the films prepared with 2% HPMC using 10% propylene glycol (F2 films). Accelerated stability studies revealed that DH showed proved stability throughout the experiment time. DH bioavailability from F2 films was determined and compared with that of the marketed oral capsules (Cymbalta® 30 mg). The pharmacokinetic results showed that Cmax for F2 was higher than the market product. In addition, ANOVA analysis showed that a Tmax of F2 film was significantly lower, while, the AUC0-72 of F2 was significantly higher than that of Cymbalta capsules. The percentage relative bioavailability of DH from F2 was found to be 296.39%. Therefore, the prepared buccal films offer an alternative route for the administration of DH with the possibility of improving its bioavailability.

Impurities in Drug Products and Active Pharmaceutical Ingredients.

Analytical methods should be selective and fast. In modern times, scientists strive to meet the criteria of green chemistry, so they choose analytical procedures that are as short as possible and use the least toxic solvents. It is quite obvious that the products intended for human consumption should be characterized as completely as possible. The safety of a drug is dependent mainly on the impurities that it contains. High pressure liquid chromatography and ultra-high pressure liquid chromatography have been proposed as the main techniques for forced degradation and impurity profiling. The aim of this article was to characterize the relevant classification of drug impurities and to review the methods of impurities determination for atorvastatin (ATV) and duloxetine (DLX) (both in active pharmaceutical ingredients and in different dosage forms). These drugs have an impact on two systems of the human body: cardiac and nervous. Simple characteristics of ATV and DLX, their properties and specificity of action on the human body, are also included in this review. The analyzed pharmaceuticals-ATV (brand name Lipiron) and DLX (brand name Cymbalta)-were selected for this study based on annual rankings prepared by Information Medical Statistics.

Application of the design of experiments in optimization of drug layering of pellets with an insight into drug polymer interactions.

This study consists of two experimental designs. Within the first one, suitable technique for application of model drug onto inactive pellets was evaluated and formulation and process parameters with greatest impact to process efficency and useful yield were determined. Results of experiments showed that formulation characteristics were the ones with the greatest impact on coating efficiency and that suspension layering technique was significantly better for drug application onto inactive pellets in comparison to solution layering during which pronounced agglomeration of pellets occurred. Analysis of drug-polymer interactions by differential scanning calorimetry was performed to explain the results of experiments. The reason for agglomeration of pellets during solution layering was formation of low Tg amorphous form of model drug. The second set of experiments was performed according to central composite design experimental plan in order to optimize level of binder and concentration of solids in the coating liquid which were found to have greatest positive impact on process efficiency and useful yield in the screening study. Statistically significant models were obtained by response surface methodology and it was possible to use them to define optimal levels of excipients in the formulation.

Chemoenzymatic synthesis of (S)-duloxetine using carbonyl reductase from Rhodosporidium toruloides.

A chemoenzymatic strategy was developed for (S)-duloxetine production employing carbonyl reductases from newly isolated Rhodosporidium toruloides into the enantiodetermining step. Amongst the ten most permissive enzymes identified, cloned, and overexpressed in Escherichia coli, RtSCR9 exhibited excellent activity and enantioselectivity. Using co-expressed E. coli harboring both RtSCR9 and glucose dehydrogenase, (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol 3a was fabricated with so far the highest substrate loading (1000mM) in a space-time yield per gram of biomass (DCW) of 22.9mmolL(-1)h(-1)gDCW(-1) at a 200-g scale. The subsequent synthetic steps from RtSCR9-catalyzed (S)-3a were further performed, affording (S)-duloxetine with 60.2% overall yield from 2-acethylthiophene in >98.5% ee.

Characterization of stress degradation products of duloxetine hydrochloride employing LC-UV/PDA and LC-MS/TOF studies.

Duloxetine HCl was subjected to forced degradation under conditions of hydrolysis (neutral, acidic and alkaline), oxidation, photolysis and thermal stress, as suggested in the ICH guideline Q1A(R2). The drug showed significant degradation under acidic, alkaline and aqueous hydrolytic as well as photolytic conditions. The drug remained stable under thermal and oxidative stress conditions. In total, seventeen degradation products (I-XVII) were formed under varied conditions, which could be separated by chromatography of respective degraded solutions on C18 (250 mm×4.6 mm; 5 µ, Nulceodur) column using isocratic elution method. Detection wavelength was selected as 290 nm. MS/TOF accurate mass studies were carried out to establish the complete fragmentation pathway of the drug and degradation products, which, in turn, was utilized in characterization of the products. The degradation pathway of the drug leading to generation of fifteen products I-X, XII-XIII, XV-XVII was postulated and this has not been reported so far.

Development of duloxetine hydrochloride loaded mesoporous silica nanoparticles: characterizations and in vitro evaluation.

This study investigated the potential use of mesoporous silica nanoparticles (MSNs) as a carrier for duloxetine hydrochloride (DX), which is prone to acid degradation. Sol-gel and solvothermal methods were used to synthesize the MSNs, which, after calcination and drug loading, were then characterized using X-ray diffraction (XRD), Brunauer-Emmett-Teller (BET) technique, thermogravimetric analysis (TGA), Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and diffuse reflectance ultraviolet-visible (DRS-UV-Vis) spectroscopy. Releases of DX from the MSNs were good in pH 7.4 (90%) phosphate buffer but poor in acidic pH (40%). In a comparative release study between the MSNs in phosphate buffer, TW60-3DX showed sustained release for 140 h, which was higher than the other nanoparticles. The mechanism of DX release from the MSNs was studied using Peppas kinetics model. The "n" value of all three MSNs ranged from 0.45 to 1 with a correlation coefficient (r (2)) >0.9, which indicated that the release of the drug from the system follows the anomalous transport or non-Fickian diffusion. The results supported the efficacy of mesoporous silica nanoparticles synthesized here as a promising carrier for duloxetine hydrochloride with higher drug loading and greater pH-sensitive release.