Water-soluble Active Pharmaceutical Ingredients Research Articles

Characterizations and Assays of α-Glucosidase Inhibition Activity on Gallic Acid Cocrystals: Can the Cocrystals be Defined as a New Chemical Entity During Binding with the α-Glucosidase?

Cocrystallization with co-former (CCF) has proved to be a powerful approach to improve the solubility and even bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, it is still uncertain whether a cocrystal would exert the pharmacological activity in the form of a new chemical entity, an API-CCF supramolecule. In the present study, gallic acid (GA)-glutaric acid and GA-succinimide cocrystals were screened. The solubility, dissolution rate and oral bioavailability of the two cocrystals were evaluated. As expected, AUCs of GA-glutaric acid and GA-succinimide cocrystals were 1.86-fold and 2.60-fold higher than that of single GA, respectively. Moreover, experimental evaluations on α-glucosidase inhibition activity in vitro and theoretical simulations were used to detect whether the two cocrystals would be recognized as a new chemical entity during binding with α-glucosidase, a target protein in hypoglycemic mechanisms. The enzyme activity evaluation results showed that both GA and glutaric acid displayed α-glucosidase inhibition activity, and GA-glutaric acid cocrystals showed strengthened α-glucosidase inhibition activity at a moderate concentration, which is attributed to synergism of the two components. Molecular docking displayed that the GA-glutaric acid complex deeply entered the active cavity of the α-glucosidase in the form of a supramolecule, which made the guest-enzyme binding configuration more stable. For the GA and succinimide system, succinimide showed no enzyme inhibition activity, however, the GA-succinimide complex presented slightly higher α-glucosidase inhibition activity than that of GA. Molecular docking simulation indicated that the guest molecules entering the active cavity of the α-glucosidase were free GA and succinimide, not the GA-succinimide supramolecule.

A Pediatrics Utilization Study in The Netherlands to Identify Active Pharmaceutical Ingredients Suitable for Inkjet Printing on Orodispersible Films.

Background: The use of medication in pediatrics, children aged 0–5 years, was explored so as to identify active pharmaceutical ingredients (APIs) suitable for inkjet printing on a plain orodispersible film (ODF) formulation in a pharmacy. Methods: The database IADB.nl, containing pharmacy dispensing data from community pharmacies in the Netherlands, was used to explore medication use in the age group of 0–5 years old, based on the Anatomical Therapeutic Chemical classification code (ATC code). Subsequently, a stepwise approach with four exclusion steps was used to identify the drug candidates for ODF formulation development. Results: there were 612 Active Pharmaceutical Ingredients (APIs) that were dispensed to the target group, mostly antibiotics. Of the APIs, 221 were not registered for pediatrics, but were used off-label. After the exclusion steps, 34 APIs were examined regarding their suitability for inkjet printing. Almost all of the APIs were sparingly water soluble to practically insoluble. Conclusion: Pharmaceutical inkjet printing is a suitable new technique for ODF manufacturing for pediatric application, however the maximal printed dose as found in the literature remained low. From the selected candidates, only montelukast shows a sufficiently high water-solubility to prepare a water-based solution. To achieve higher drug loads per ODF is ambitious, but is theoretically possible by printing multiple layers, using highly water-soluble APIs or highly loaded suspensions.

Phase behavior of pharmaceutically relevant polymer/solvent mixtures.

In the pharmaceutical industry, polymers are used as excipients for formulating poorly water-soluble active pharmaceutical ingredients (APIs) in so-called "amorphous solid dispersions" (ASDs). ASDs can be produced via solvent-based processes, where API and polymer are both dissolved in a solvent, followed by a solvent evaporation step (e.g. spray drying). Aiming at a homogeneous API/polymer formulation, phase separation of the components (API, polymer, solvent) during solvent evaporation must be avoided. The latter is often determined by the phase behavior of polymer/solvent mixtures used for ASD processing. Therefore, this work investigates the polymer-solvent interactions in these mixtures. Suitable polymer/solvent combinations investigated in this work comprise the pharmaceutically relevant polymers poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64), and hydroxyppropyl methylcellulose acetate succinate 126G (HPMCAS) as well as the solvents acetone, dichloromethane (DCM), ethanol, ethyl acetate, methanol, and water. Based on vapor-sorption experiments demixing of solvents and polymers were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These were found to be correct for all investigated solvent/polymer mixtures. Acetone, DCM, ethanol, methanol, and water were found to be completely miscible with PVPVA64. DCM, ethanol, methanol, and water were found to be completely miscible with PVP K90, while none of the investigated solvents was appropriate for avoiding immiscibility with HPMCAS. In addition, the impact of temperature, polymer molecular weight, and solvent-mixture composition on miscibility was successfully predicted using PC-SAFT. Thus, the proposed methodology allows identifying suitable solvents or solvent mixtures relevant for solvent-based preparations of pharmaceutical ASD formulations with low experimental effort.

Impact of process parameters on particle morphology and filament formation in spray dried Eudragit L100 polymer

Spray drying is one of the most broadly applicable and widely used methods of producing amorphous solid dispersions (ASDs). ASDs can improve the oral absorption of poorly water-soluble active pharmaceutical ingredients. Eudragit L100 is an appealing ASD excipient, due to its favorable impact on ASD physical stability and dissolution performance. However, spray drying Eudragit L100 can lead to high-aspect ratio filaments which reduce flowability, density and yield of the resulting powder. This negatively impacts downstream ASD performance and dosage form manufacturability. This work presents a mechanism for filament formation, which results in a particle engineering design space of key processing parameters, defined by a dimensionless parameter for assessing filament formation risk. Specifically, it was found that solution concentration, spray dryer inlet temperature and solvent volatility had the largest impact on controlling filament formation, based on their influence on the relative time scale to atomize versus droplet skinning during drying.

Drug amorphisation by fluid bed hot-melt impregnation of mesoporous silica carriers

• Solvent-free process for converting crystalline drug to amorphous form. • Successful co-fluidisation of ibuprofen and mesoporous silica particles. • No recrystallisation for drug loadings up to 50% wt. • Exceptional dissolution rate enhancement at both acidic and neutral pH. Amorphisation using mesoporous inorganic carriers represents an emerging formulation strategy for the dissolution rate enhancement of poorly water-soluble Active Pharmaceutical Ingredients (APIs). This approach employs API loading to a porous carrier, which stabilises the amorphous form and prevents recrystallisation due to spatial confinement in the mesopores. In this work, we utilise recently discovered silica particles with a unique pore structure that contain well-connected macropores for rapid capillary transport of the molten API, alongside mesopores for efficient drug amorphisation. We demonstrate that these particles enable efficient drug loading by a solvent-free process, namely hot-melt impregnation in a fluidised bed reactor. By controlling the process temperature and therefore the melt-in rate of the API, we show that the co-fluidisation of the API source crystals and silica carrier particles is possible without wall build-up or agglomeration. Using ibuprofen as a model API, we systematically investigate the effect of drug loading (30–50% w/w) and process conditions (heating time, process temperature) on the physico-chemical and dissolution properties of the product. The amorphous content of the silica particles after drug loading was established by DSC and XRPD and the chemical stability was confirmed by FTIR spectroscopy. More than a five-fold dissolution rate enhancement compared to crystalline API was achieved by fluid bed amorphisation.

Tailor-made solvents for pharmaceutical use? Experimental and computational approach for determining solubility in deep eutectic solvents (DES)

A deep eutectic solvent (DES) is a mixture of two or more chemicals that interact via hydrogen bonding and has a melting point far below that of the individual components. DESs have been proposed as alternative solvents for poorly soluble active pharmaceutical ingredients (API). In this study, the solvation capacities of six deep eutectic solvents were compared to water and three conventional pharmaceutical solvents (PEG 300, ethanol and glycerol) for 11 APIs. The experimentally determined solubilities were compared to computational solubilities predicted by the Conductor-like Screening Model for Real Solvents (COSMO-RS). While the conventional pharmaceutical solvents PEG 300 and ethanol were the best solvents for the majority of the studied APIs, API-DES combinations were identified, which exceeded the API solubility found in the conventional pharmaceutical solvents. Furthermore, it was also possible to obtain high solubilities in the DESs relative to water, suggesting DESs to be potential solvents for poorly water soluble APIs. In addition, the relative increase in solubility found in the experimental data could be well predicted ab initio using COSMO-RS. Hence, COSMO-RS may in the future be used to reduce the experimental screening of potential DESs for a given API.

Acoustic cavitation assisted hot melt mixing technique for solid lipid nanoparticles formulation, characterization, and controlled delivery of poorly water soluble drugs

The motive of the present study was to enhance the bioavailability of poorly water soluble active pharmaceutical ingredients (APIs) through by making solid lipid nanoparticles (SLNs) using acoustic cavitation assisted hot melt mixing method. Here, we investigated the efficacy of this technique for preparation of SLNs loaded with different drugs. To achieve the high entrapment efficiency and drug loading, the effect of the ratio of lipid to emulsifier on SLNs’ properties and their performance were studied. The solid state of drugs in formulated solid lipid nanoparticles was characterize using several advanced characterization techniques. As the emulsifier concentration increases, decreased in particle size was observed. We achieved the high entrapment efficiency (more than 80%) and drug loading (4.9–5.4%) at optimum lipid to emulsifier ratio 7:4 and 10% (w/w) drug concentration. The formulated drug loaded solid lipid nanoparticles showed good biocompatibility against Raw 264.7 cells and nearly 100% drug was release at end of day-3. It is concluded that acoustic cavitation assisted hot melt mixing method suitable for formulation of SLNs. Hence, it is evident that the better performance of formulated SLNs of poorly water soluble APIs loaded tristearin nanoparticles in vitro and could be developed further for clinical studies.

Co amorphous valsartan nifedipine system: Preparation, characterization, in vitro and in vivo evaluation

Co amorphous systems are supersaturated drug delivery systems which offer a basic platform for delivery of multicomponent adducts (combination of more than one active pharmaceutical ingredient (API)) and/or as a fixed dose combination therapy, in addition to their potential to improve the apparent solubility, dissolution rate and ultimately bioavailability of poorly water soluble APIs. In the present work, a new drug-drug co amorphous system namely valsartan–nifedipine was prepared by quench cooling technique. Prepared co amorphous system was characterized for its solid state behavior with the help of Fourier Transform Infrared spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and Powder X Ray Diffractometry (PXRD). The optimized co amorphous system was stable for 1 month when exposed to accelerated stability condition (40 ± 2 °C and 75 ± 5% RH). The improved stability of amorphous nifedipine in co amorphous system was attributed to improved miscibility and intra and intermolecular non-covalent interactions mainly due to presence of hydrogen bonding between valsartan and nifedipine which was studied by FTIR analysis. Co amorphous systems were evaluated by mainly in vitro dissolution and in vivo benefit. In vitro dissolution study showed nearly 5.66 folds and 1.61 folds improvement which was translated to 3.63 and 2.19 times enhancement in vivo Cmax for nifedipine and valsartan respectively.

Preparation of submicron drug particles via spray drying from organic solvents.

Manufacturing poorly water-soluble active pharmaceutical ingredients (API) with sufficient bioavailability is a significant challenge in pharmaceutical research. A higher bioavailability can reduce both the applied dosage and the side effects for the patient. One method of increasing the bioavailability is to reduce the particle size of the drug down to the nanoscale. An innovative procedure for the preparation of particles in the submicron size range is spray drying with aerosol conditioning, followed by subsequent separation of the particles in an electrostatic precipitator (ESP). This process has been tested before in an earlier work with aqueous model substances at high production rates (1 g/h) and narrow particle-size distributions (mannitol: d50,0 = 455 nm, span = 0,8) in the submicron range. Spray drying from an aqueous solution with low drug concentrations (<1 wt-%) leads to particles in the lower nanosize range, but the low concentrations make this process inefficient. A custom-made plant was modified in order to handle the organic spray-drying process. In addition, explosion protection had to be considered. This work focuses on the spray drying of submicron particles from organic solvents for the purpose of increasing the dissolution rate of the API griseofulvin. API particles were successfully produced in the submicron size-range, characterized and the dissolution behavior was investigated. The dissolution time to dissolve 80% of the drug, t80, was reduced from 21.5 min for the micronized grade API to 8.5 min for the submicron product.

Sensitivity of a continuous hot-melt extrusion and strand pelletization line to control actions and composition variation

The purpose of this work was to develop a robust hot-melt extrusion and strand pelletization process for manufacturing pellets with an immediate release (IR) of a poorly water-soluble active pharmaceutical ingredient (API), nimodipine. The robustness of pharmaceutical continuous manufacturing processes and of its control strategy is vital for competitiveness to traditional batch-manufacturing. Therefore, first the sensitivity of product quality, process stability, and process monitoring tools to i) parameter changes due to control actions and ii) typical process deviations, i.e., feeding errors, was investigated in a design of experiments (DoE). Thereby, die melt pressure was found to be highly sensitive to composition deviations, i.e. a limiting factor for process stability. Especially critical were deviations to increased HPMC content, since it behaved as a filler in the melt. Pelletization, or pellet size and size distribution respectively, were found to be sensitive to an increased throughput, due to the resulting insufficient strand cooling before the pelletizer. API dissolution in contrast, was found to be robust across the entire investigated range of formulation and process settings. Second, a design space for the production of IR pellets for subsequent tableting was established, and finally, a technical control strategy was developed to ensure a robust process. Near-infrared (NIR) spectroscopy was applied to monitor API content and the sensitivity of the residence time distribution (RTD) was investigated by means of tracer measurements. NIR-based API content monitoring and RTD models for material tracking were found to be at risk after processing melt with high HPMC content, due to a lack of purging by less viscous formulation compositions.

Continuous and Scalable Process for the Production of Hollow Crystals of a Poorly Water-Soluble Active Pharmaceutical Ingredient for Dissolution Enhancement and Inhaled Delivery

This study reports a new technique for the manufacture of micron-sized, hollow crystals of a poorly water-soluble pharmaceutical compound, spironolactone, by a continuous and scalable antisolvent p...

A Novel Approach to Evaluate Amorphous-to-Crystalline Transformation of Active Pharmaceutical Ingredients in Solid Dispersion Using Time-Domain NMR.

The aim of this study was to demonstrate the usefulness of the time-domain NMR (TD-NMR) method to characterize the crystalline state of active pharmaceutical ingredients (APIs) containing a solid dispersion. In this study, indomethacin (IMC) was used as a model for poorly water-soluble API. Solid dispersions of IMC were prepared with polyvinylpyrrolidone (PVP) at different weight ratios. First, we measured the T1 relaxation behavior of solid dispersions. From the result, the T1 relaxation time (T1) changed according to the API content; the T1 tended to increase with increasing API content because the T1 value of amorphous IMC was longer than that of PVP. Next, we tried to monitor the amorphous-to-crystalline transformation of IMC in the solid dispersion during the thermal stress test. In the case of solid dispersion containing 90% IMC, a clear prolongation of the T1 could be observed during the thermal stress test. From the powder X-ray diffraction patterns, the change in T1 relaxation behavior must be caused by the IMC transformation from amorphous to crystalline. From these findings, we were successful in monitoring the IMC amorphous-to-crystalline transformation by the changes in T1 relaxation behavior. Our findings led us to conclude that TD-NMR is a novel approach for the evaluation of crystalline state of APIs in solid dispersions.

Model-based description of disintegration time and dissolution rate of nanoparticle-loaded orodispersible films

The embedding of nanoparticles in orodispersible films (ODFs) is an innovative strategy to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (API). As the films are supposed to disintegrate within seconds when placed in the mouth, the disintegration time of the ODFs as well as the dissolution behavior of the API are of great interest. This study introduces a new possibility for a model-based description of these film properties to enable a prediction for the process layout for the manufacturing of the nanoparticle-loaded ODFs. Furthermore, this fundamental understanding can provide information on process robustness as a tool applied in future Quality by Design (QbD) approaches.The disintegration times of the nanoparticle-containing ODFs were measured with the SFaB method (slide frame and ball) and could be mathematically described considering the impact of the particle load and the dry film thickness on the disintegration behavior. Furthermore, it is considered if the films are disintegrated at the calculated time with a probability of 50% or any other probability. Besides the disintegration time, a clear influence of film parameters like the particle load, size of the embedded particles, film thickness and sample sizes was shown which affect the dissolution rate of the API from the ODF. The second model developed in the study identified a clear correlation between the total surface area of API particles in the film and the dissolution rate of the API, to predict the time period needed to release the API embedded in the ODFs.

Electrospun nanofiber-based niflumic acid capsules with superior physicochemical properties

The aim of this study was to assess whether nanofibrous drug mats have potential as delivery systems for poorly water-soluble drugs. Amorphous nanofiber mats from a model poorly water-soluble active pharmaceutical ingredient (API), niflumic acid, together with the polymer excipient, polyvinyl pyrrolidine, were prepared by nozzle-free electrospinning. This technique offers a scalable way for drug formulation, and by increasing the surface area of the drug, the dissolution rate and therefore bioavailability of the API can be improved. In this study, both the amount of the dissolved active ingredient and the dissolution kinetics has been improved significantly when the nanofibrous mats were used in the drug formulation. A 15-fold increase in the dissolved amount of the produced amorphous niflumic acid nanofiber was observed compared to the dissolved amount of the raw drug within the first 15 min. Capsule formulation was made by mixing the electrospun nanofibers with a microcrystalline cellulose filler agent. When comparing the dissolution rate of the capsule formulation on the market with the nanofibrous capsules, a 14-fold increase was observed in the dissolved drug amount within the first 15 min.

Nano and micro dispersions of two-phase amorphous-amorphous drug formulations as strategy to enhance solubility of pharmaceuticals

Abstract Preparation of amorphous solid dispersions (ASD) has been widely used as a strategy to improve the solubility of poorly water-soluble active pharmaceutical ingredients (API). However, immiscibility between a drug and an excipient has been the basis for dismissal of some systems to produce ASDs, because it was believed that phase separation might induce undesired crystallization. In a recent study, we reported that immiscibility between a drug and an excipient matrix can actually be used as an advantage to reduce the particle size of the dispersed drug, thus improving its distribution in the excipient to obtain thermally stable two-phase amorphous-amorphous solid dispersions (AASD) increasing the API’s solubility. This preparation focused on a single API; therefore, with the purpose to prove that this novel strategy can be extended to other drugs, in the present work, new amorphous-amorphous simvastatin-glucose (SVS-GLU) solid dispersion were prepared by the melt-quenching technique assisted by ultrasound. This work demonstrates that the application of ultrasound during the preparation of AASD reduces the API’s particle size and produces a homogeneous distribution of the drug in the matrix, enhancing SVS’s aqueous solubility almost four times, compared with its crystalline form. Furthermore, the amorphous state of the formulation was found to be stable under storage conditions, as evaluated by powder X-ray diffraction. These studies give rise to formulations that can be introduced as novel alternatives to produce thermally stable systems and enhance the solubility of poorly water-soluble drugs.

Carrier particle mediated stabilization and isolation of valsartan nanoparticles.

Drug nanoparticles are a promising solution to the challenging issues of low dissolution rates and erratic bioavailability due to their greater surface/volume ratio. The central purpose of this study is to prepare, stabilize and isolate nanoparticles of poorly water-soluble active pharmaceutical ingredients (APIs) into a dried form with the help of clay carrier particles. Isolation of nanoparticles from suspension into the dried state is crucial to avoid the problems of aggregation and Ostwald ripening. In this study nanoparticles of the API valsartan were generated via a reverse antisolvent process at high supersaturations. Montmorillonite (MMT) and protamine functionalized montmorillonite (PA-MMT) were employed for stabilization and isolation of the valsartan (Val) nanoparticles (ca. 50 nm) into a dried form. A high dissolution rate of the resultant solid formulation at high drug loadings (up to 33.3% w/w) was achieved. The dissolution rates of the isolated valsartan nanoparticle carrier composites (dried Val-MMT nanocomposites and dried Val-PA-MMT nanocomposites) were similar to that of freshly prepared suspended valsartan nanoparticles, confirming that the high surface area of the nanoparticles is retained during the adsorption and drying processes. Differential scanning calorimetry and PXRD studies indicated that the valsartan nanoparticles were amorphous when adsorbed onto the carrier particles. The dissolution rates of the Val-MMT and Val-PA-MMT nanocomposites were maintained after 10 months' storage which indicates that no aggregation or solid state transformation of the carrier-stabilized Val nanoparticles had occurred.

Effect of solvent selection on drug loading and amorphisation in mesoporous silica particles

Increasing the dissolution rate of poorly water-soluble active pharmaceutical ingredients (APIs) is a key strategy used for improving their oral bioavailability. One of the formulation approaches is API loading to mesoporous carrier particles, which can increase the dissolution rate through the combination of improved powder wettability and dispersion, higher surface area, and API conversion from crystalline to the amorphous state. From the formulation process point of view, the maximum achievable drug loading is a crucial parameter, which depends on the loading method. Drug loading by sorption from a solution is a technologically attractive approach, since it involves familiar unit operations (mixing, filtration, drying). However, the success of the equilibrium sorption approach depends on the choice of the solvent. In this work we present an experimental study of loading efficiency to mesoporous silica particles, based on a set of 10 APIs combined with 6 different solvents at a range of concentrations. We show that due to the competitive nature of the adsorption process, the solvent with the highest API solubility is not necessarily the best candidate for maximising the API loading. Based on the investigated drug-solvent combinations, we show that the dielectric constant of the solvent is a good predictor of loading efficiency and can be used as a general guideline for solvent selection. On the other hand, we did not find any systematic correlation between commonly measured API properties such as logP and their loading efficiency.

Increasing bioavailability of very poorly water-soluble compounds. A case study of an anti-tumor drug, soloxolon methyl

Many potential drug candidates are excluded from consideration at the early stages of research and development because of their poor solubility in the biological fluids. Even toxicological tests in vivo become impossible, since there is no way to administer the drug to an animal. The purpose of this study was to explore the feasibility of developing bioavailable formulations of very poorly soluble compounds like soloxolon methyl (water solubility <0.3 μg/ml, 6∙10–13 M). The three-component solid dispersions were prepared by freeze-drying of β-glycine suspensions in a solution of soloxolon methyl and polyethylene glycol in tert-butanol. The β-glycine played the role of a disintegrant, and polyethylene glycol – of a carrier. The cytotoxic activity was tested in vitro with respect to human cervical carcinoma cells; hematological toxicity was tested in vivo on mice. Soloxolon methyl solubility from the formulations increased ∼25–10 times (7.3–3.1 vs 0.3 μg/ml), whereas the half maximal inhibitory concentration decreased 1.3–1.9 times as compared with сrude soloxolon methyl. The in vivo testing has shown the absence of hematological toxicity. The methodology described in this work is transferrable to other poorly water-soluble active pharmaceutical ingredients that cannot be micronized/solubilized by routine techniques in a straightforward way.

Choosing Appropriate Solvents for ASD Preparation.

Amorphous solid dispersions (ASDs) are often used for formulating poorly water-soluble active pharmaceutical ingredients (APIs). In an ASD, the amorphous API is embedded in a suitable matrix excipient in order to stabilize the amorphous state and control the dissolution performance. ASDs can be prepared by commonly dissolving the API and the polymer in a suitable organic solvent which is evaporated afterward (e.g., via spray drying) aiming at a homogeneous API distribution in the polymer matrix. Sometimes, unexpected solvent influences on the heterogeneity of the dry ASD are observed. Thermodynamic predictions using the Perturbed-Chain Statistical Associating Fluid Theory combined with experimental investigations via Raman spectroscopy, differential scanning calorimetry, and microscopy performed in this work revealed the amorphous phase separation (APS) between the solvent and the polymer as causing the ASD heterogeneities. It will be shown that thermodynamic modeling allows for identifying appropriate solvents that will neither show APS with the polymeric excipient nor at any time of the drying process of ASD formulations.

Dissolution improvement of an active pharmaceutical ingredient in a polymer melt by hot melt extrusion

Abstract Dissolution of poorly water-soluble active pharmaceutical ingredients (APIs) in polymeric melts plays an important role in the manufacturing of solid dispersions and solid solutions. The understanding of the dissolution is essential for selecting the processing equipment, the operating conditions, and the polymer excipients. The methodology presented in this work for ketoprofen (KTO) and polymer excipients serves as a screening process to select the best API-polymer formulation for hot melt extrusion (HME) to target a specific release profile. KTO dispersion within the polymer was characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), and dissolution tests. Thermal characterization shows that a single phase amorphous solid solution (one glass transition temperature [Tg]) was achieved under the HME processing conditions and screw configuration; and with the combination of polymer excipients, an extended release profile of KTO was accomplished, releasing 100% of KTO in 24 h.