Powder bed fusion-laser beam (PBF-LB) three-dimensional (3D) printing: Influence of laser hatching distance on the properties of zolpidem tartrate tablets.

Laser sintering, known as powder bed fusion-laser beam (PBF-LB), offers promising potential for the fabrication of patient-specific drugs. The aim of this study was to provide an insight into the PBF-LB process with regard to the process parameters, in particular the laser hatching distance, and its influence on the properties of zolpidem tartrate (ZT) tablets. PHARMACOAT® 603 was used as the polymer, while Candurin® Gold Sheen and AEROSIL® 200 were added to facilitate 3D printing. The particle size distribution of the powder blend showed that the layer height should be set to 100 µm, while the laser hatching distance was varied in five different steps (50, 100, 150, 200 and 250 µm), keeping the temperature and laser scanning speed constant. Increasing the laser hatching distance and decreasing the laser energy input led to a decrease in the colour intensity, mass, density and hardness of the ZT tablets, while the disintegration and dissolution rate were faster due to the more fragile bonds between the particles. The laser hatching distance also influenced the ZT dosage, indicating the importance of this process parameter in the production of presonalized drugs. The absence of drug-polymer interactions and the amorphization of the ZT were confirmed.

Formulation and characterization of immediate-release oral dosage forms with zolpidem tartrate fabricated by digital light processing (DLP) 3D printing technique.

The introduction of three-dimensional (3D) printing in the pharmaceutical field has made great strides towards innovations in the way drugs are designed and manufactured. In this study, digital light processing (DLP) technique was used to fabricate oral dosage forms of different shapes with zolpidem tartrate (ZT), incorporated within its therapeutic range. Formulation factors, such as poly(ethylene glycol) diacrylate (PEGDA) and poly(ethylene glycol) 400 (PEG 400) ratio, as well as water content, were varied in combination with the surface area/volume (SA/V) ratio to achieve immediate drug release. Hypromellose (HPMC) was used as a stabilizing agent of photoreactive suspensions in an attempt to prevent drug sedimentation and subsequent variations in drug content uniformity. Oral dosage forms with doses in the range from 0.15 mg to 6.37 mg, showing very rapid and rapid drug dissolution, were successfully fabricated, confirming the potential of this technique in drug manufacturing with the ability to provide flexible dose adjustments and desirable release profiles by varying formulation factors and geometry of 3D models. DSC (differential scanning calorimetry), XRPD (X-ray powder diffraction) and scanning electron microscopy (SEM) showed that ZT remained in a crystalline form within printed dosage forms and no interactions were found between ZT and polymers.

Improving Tableting Performance of Lactose Monohydrate by Fluid-Bed Melt Granulation Co-Processing.

Co-processing is commonly used approach to improve functional characteristics of pharmaceutical excipients to become suitable for tablet production by direct compression. This study aimed to improve tableting characteristics of lactose monohydrate (LMH) by co-processing by fluid-bed melt granulation with addition of hydrophilic (PEG 4000 and poloxamer 188) and lipophilic (glyceryl palmitostearate) meltable binders. In addition to binding purpose, hydrophilic and lipophilic excipients were added to achieve self-lubricating properties of mixture. Co-processed mixtures exhibit superior flow properties compared to pure LMH and comparable or better flowability relative to commercial excipient Ludipress®. Compaction of mixtures co-processed with 20% PEG 4000 and 20% poloxamer 188 resulted in tablets with acceptable tensile strength (>2 MPa) and good lubricating properties (ejection and detachment stress values below 5 MPa) in a wide range of compression pressures. While the best lubricating properties were observed when glyceryl palmitostearate was used as meltable binder, obtained tablets failed to fulfil required mechanical characteristics. Although addition of meltable binder improves interparticle bonding, disintegration time was not prolonged compared to commercial excipient Ludipress®. Co-processed mixtures containing 20% of either PEG 4000 or poloxamer 188 showed superior tabletability and lubricant properties relative to LMH and Ludipress® and can be good candidates for tablet production by direct compression.

Potential application of low molecular weight excipients for amorphization and dissolution enhancement of carvedilol.

In this study, four low molecular weight (LMW) excipients, tryptophan (TRY), phenylalanine (PHE), lysine (LYS) and saccharin (SAC) were evaluated as co-formers to generate co-amorphous systems (CAMS) by ball milling with carvedilol (CRV). Mixtures of CRV and LMW excipient in 1:0.5, 1:1 and 1:2 drug:excipient molar ratios were ball milled and analysed by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform (FT-IR) infrared spectroscopy and dissolution testing. CAMS were formed by milling of a mixture of CRV with TRY in 1:2 M ratio and SAC in 1:1 M ratio, while amorphization of only CRV was achieved in other mixtures with SAC. In other samples containing TRY and PHE, milling resulted in partial amorphization, while LYS was the least suitable excipient for the amorphization of CRV. Unexpectedly, the highest supersaturation of CRV was achieved from samples containing CRV and LYS in 1:1 and 1:2 M ratios, despite the absence of a significant reduction in CRV crystallinity upon milling of these samples. Increase of hydrophobic surface area caused by milling of samples with TRY and PHE and agglomeration during dissolution testing of samples containing SAC are likely causes of poor dissolution performance of mixtures containing fully or partially amorphous CRV.

Enhanced antimicrobial activity and physicochemical stability of rapid pyro-fabricated silver-kaolinite nanocomposite.

The present research aims to enhance the antimicrobial activity of kaolinite surfaces by a one-step cost-effective and energy-efficient dry thermal reaction, producing an antibacterial and antifungal silver-kaolinite (Ag-Kao) nanocomposite agent. Pharmaceutical grade kaolin powder samples, with variable kaolinite structural order-disorder degree, were homogeneously mixed with silver nitrate in a proportion 1:4 AgNO3:kaolin (w/w) and sintered at 400 °C for 30 min. The composition, microstructure, microtexture and surface characteristics of the pyro-fabricated nanocomposites were characterized by XRD/XRF diffractometry, differential scanning calorimetry DSC, FT-IR spectroscopy, TEM/EDX, zeta potential (mV) measured within the 2-12 pH range, and BET method. Physicochemical stability was evaluated by silver dissociation testing under close-neutral and acidic conditions with Ag content assay using ICP-OES. The resulting Ag-Kao nanocomposites exhibited bulk silver contents ranging from 9.29% to 13.32% with high physicochemical stability in both neutral and acidic mediums (Ag dissociation rate <0.5% in 5 days). Ag nanocrystals exhibited particle sizes ranging from 5 to 30 nm, which were embedded and reinforced within the kaolinite matrix. The sizes of the Ag nanocrystals and their distribution patterns on the edges and faces of kaolinite platelets were controlled by the structural order-disorder degree. Highly ordered kaolinites (Hinckley Index, HI > 1) produced platelet edge-clustered silver nanocrystals due to the abundance of the dangling hydroxyls on platelet edges, while the highly disordered kaolinite (HI < 1) provided homogeneous platelet basal-doped silver nanocrystals due to the presence of some residual charges by exposed basal hydroxyl groups with interplatelet silver diffusivity. At pH 2, the magnitude of the positive surface charge was influenced by the silver nanocrystal size. Nanocomposites with the smallest silver nanocrystals (10-5 nm) exhibited the highest positive zeta potential (+15.2 mV to +17.0 mV), while those with larger silver nanocrystals (up to 30 nm) indicated lower positive zeta potential values (+9.5 mV to +3.6 mV). Under the same testing conditions using the Mueller-Hinton broth microdilution method, the raw kaolin samples did not show any significant antimicrobial activity, while all the pyro-fabricated Ag-Kao nanocomposite samples showed potent antibacterial and antifungal activity at low doses (MIC range 0.1-0.0125 mg/mL). Therefore, modulation of the effective electrostatic surface charge of the kaolinite platelets, via thermal doping of silver within their basal planes and edges, was found to be strongly dependent on the pH as well as the size and microtexture of the silver nanocrystals (mainly controlled by the order-disorder degree HI). The resulting modified nanostructure, with physicochemical stability and the efficient surface properties of the designed pyro-fabricated nanocomposite, led to an enhanced synergistic biophysical antimicrobial activity.

Digital Light Processing (DLP) 3D Printing of Atomoxetine Hydrochloride Tablets Using Photoreactive Suspensions.

Three-dimensional (3D) printing technologies are based on successive material printing layer-by-layer and are considered suitable for the production of dosage forms customized for a patient's needs. In this study, tablets of atomoxetine hydrochloride (ATH) have been successfully fabricated by a digital light processing (DLP) 3D printing technology. Initial materials were photoreactive suspensions, composed of poly(ethylene glycol) diacrylate 700 (PEGDA 700), poly(ethylene glycol) 400 (PEG 400), photoinitiator and suspended ATH. The amount of ATH was varied from 10.00 to 25.00% (w/w), and a range of doses from 12.21 to 40.07 mg has been achieved, indicating the possibility of personalized therapy. The rheological characteristics of all photoreactive suspensions were appropriate for the printing process, while the amount of the suspended particles in the photoreactive suspensions had an impact on the 3D printing process, as well as on mechanical and biopharmaceutical characteristics of tablets. Only the formulation with the highest content of ATH had significantly different tensile strength compared to other formulations. All tablets showed sustained drug release during at least the 8h. ATH crystals were observed with polarized light microscopy of photoreactive suspensions and the cross-sections of the tablets, while no interactions between ATH and polymers were detected by FT-IR spectroscopy.

Tableting properties of microcrystalline cellulose obtained from wheat straw measured with a single punch bench top tablet press.

The objective of this work was to study the relation between the manufacturing conditions of microcrystalline cellulose (MCC), its physicochemical properties and its tableting behavior. Two different preparation procedures were used to produce MCC from wheat straw, utilizing an acid hydrolysis method, either using only sulfuric acid or combination of sulfuric and hydrochloric acid. The tableting behavior of obtained MCC samples and mixtures of MCC with ibuprofen was studied using a dynamic powder compaction analyzer. It was observed that some of the obtained MCC samples showed better flowing properties than commercially available Vivapur® PH101 and also very high values of tensile strength, solid fraction and elastic recovery. This can be linked with its good compaction behavior, but on the other hand it can cause problems with the disintegration of the tablets. In mixtures with ibuprofen, MCC samples showed lower values of tensile strength, while on the other hand elastic recovery did not seem to be much affected, still exhibiting very high values. According to the obtained results, it can be concluded that MCC obtained from the agricultural waste could have satisfactory properties for tablet preparation by the direct compression method. Further studies are needed to optimize process conditions in order to achieve better physicochemical characteristics, especially in terms of elastic recovery.

Insight into the Formation of Glimepiride Nanocrystals by Wet Media Milling.

Nanocrystal formation for the dissolution enhancement of glimepiride was attempted by wet media milling. Different stabilizers were tested and the obtained nanosuspensions were solidified by spray drying in presence of mannitol, and characterized regarding their redispersibility by dynamic light scattering, physicochemical properties by differential scanning calorimetry (DSC), FT-IR spectroscopy, powder X-ray diffraction (PXRD), and scanning electron microcopy (SEM), as well as dissolution rate. Lattice energy frameworks combined with topology analysis were used in order to gain insight into the mechanisms of particle fracture. It was found that nanosuspensions with narrow size distribution can be obtained in presence of poloxamer 188, HPC-SL and Pharmacoat® 603 stabilizers, with poloxamer giving poor redispersibility due to melting and sticking of nanocrystals during spray drying. DSC and FT-IR studies showed that glimepiride does not undergo polymorphic transformations during processing, and that the milling process induces changes in the hydrogen bonding patterns of glimepiride crystals. Lattice energy framework and topology analysis revealed the existence of a possible slip plane on the (101) surface, which was experimentally verified by PXRD analysis. Dissolution testing proved the superior performance of nanocrystals, and emphasized the important influence of the stabilizer on the dissolution rate of the nanocrystals.

Tailoring Atomoxetine Release Rate from DLP 3D-Printed Tablets Using Artificial Neural Networks: Influence of Tablet Thickness and Drug Loading.

Various three-dimensional printing (3DP) technologies have been investigated so far in relation to their potential to produce customizable medicines and medical devices. The aim of this study was to examine the possibility of tailoring drug release rates from immediate to prolonged release by varying the tablet thickness and the drug loading, as well as to develop artificial neural network (ANN) predictive models for atomoxetine (ATH) release rate from DLP 3D-printed tablets. Photoreactive mixtures were comprised of poly(ethylene glycol) diacrylate (PEGDA) and poly(ethylene glycol) 400 in a constant ratio of 3:1, water, photoinitiator and ATH as a model drug whose content was varied from 5% to 20% (w/w). Designed 3D models of cylindrical shape tablets were of constant diameter, but different thickness. A series of tablets with doses ranging from 2.06 mg to 37.48 mg, exhibiting immediate- and modified-release profiles were successfully fabricated, confirming the potential of this technology in manufacturing dosage forms on demand, with the possibility to adjust the dose and release behavior by varying drug loading and dimensions of tablets. DSC (differential scanning calorimetry), XRPD (X-ray powder diffraction) and microscopic analysis showed that ATH remained in a crystalline form in tablets, while FTIR spectroscopy confirmed that no interactions occurred between ATH and polymers.

Hydrophilic excipients in digital light processing (DLP) printing of sustained release tablets: Impact on internal structure and drug dissolution rate.

Three-dimensional (3D) printing enables the production of different objects adjusted for the specific application, which has particular importance of providing personalized therapy, whereby the challenge is to apply pharmaceutical materials into 3D printing technology. In this study, effect of poly(ethylene glycol) 400 (PEG 400), sodium chloride (NaCl), and mannitol, as hydrophilic excipients, was investigated in order to overcome very slow and incomplete drug release from tablets (printlets) fabricated by photopolymerization using digital light processing (DLP) technology. Paracetamol (acetaminophen) was used as a model drug, while polyethylene glycol diacrylate (PEGDA) was used as a photopolymer and diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide as a photoinitiator in photoreactive mixtures. Most of printlet formulations exhibit sustained release over 8 h, wherein drug release kinetics is the best described with Korsmeyer-Peppas kinetics. Variation in the content of photopolymer and excipients had an influence on the dissolution rate, mechanical characteristics, and internal structure of the investigated samples. The addition of hydrophilic polymers increased drug release rate, while PEGDA had the greatest influence on the tensile strength of printlets. The results indicate the possibility of implementation of traditional excipients into different formulations for photopolymerization based 3D printing for the production of small batches of tablets with tailored drug release.

Optimization and Prediction of Ibuprofen Release from 3D DLP Printlets Using Artificial Neural Networks.

The aim of this work was to investigate effects of the formulation factors on tablet printability as well as to optimize and predict extended drug release from cross-linked polymeric ibuprofen printlets using an artificial neural network (ANN). Printlets were printed using digital light processing (DLP) technology from formulations containing polyethylene glycol diacrylate, polyethylene glycol, and water in concentrations according to D-optimal mixture design and 0.1% w/w riboflavin and 5% w/w ibuprofen. It was observed that with higher water content longer exposure time was required for successful printing. For understanding the effects of excipients and printing parameters on drug dissolution rate in DLP printlets two different neural networks were developed with using two commercially available softwares. After comparison of experimental and predicted values of in vitro dissolution at the corresponding time points for optimized formulation, the R2 experimental vs. predicted value was 0.9811 (neural network 1) and 0.9960 (neural network 2). According to difference f1 and similarity factor f2 (f1 = 14.30 and f2 = 52.15) neural network 1 with supervised multilayer perceptron, backpropagation algorithm, and linear activation function gave a similar dissolution profile to obtained experimental results, indicating that adequate ANN is able to set out an input-output relationship in DLP printing of pharmaceutics.

Analytical and Computational Methods for the Estimation of Drug-Polymer Solubility and Miscibility in Solid Dispersions Development.

The development of stable solid dispersion formulations that maintain desired improvement of drug dissolution rate during the entire shelf life requires the analysis of drug-polymer solubility and miscibility. Only if the drug concentration is below the solubility limit in the polymer, the physical stability of solid dispersions is guaranteed without risk for drug (re)crystallization. If the drug concentration is above the solubility, but below the miscibility limit, the system is stabilized through intimate drug-polymer mixing, with additional kinetic stabilization if stored sufficiently below the mixture glass transition temperature. Therefore, it is of particular importance to assess the drug-polymer solubility and miscibility, to select suitable formulation (a type of polymer and drug loading), manufacturing process, and storage conditions, with the aim to ensure physical stability during the product shelf life. Drug-polymer solubility and miscibility can be assessed using analytical methods, which can detect whether the system is single-phase or not. Thermodynamic modeling enables a mechanistic understanding of drug-polymer solubility and miscibility and identification of formulation compositions with the expected formation of the stable single-phase system. Advance molecular modeling and simulation techniques enable getting insight into interactions between the drug and polymer at the molecular level, which determine whether the single-phase system formation will occur or not.

Selection of the suitable polymer for supercritical fluid assisted preparation of carvedilol solid dispersions.

Solid dispersions production is one of the substantial approaches for improvement of poor drug solubility. Additionally, supercritical fluid assisted method for preparation of solid dispersions can offer many advantages in comparison to the conventional melting or solvent-evaporation methods. Miscibility analysis provides valuable guidance for selection of the most appropriate polymeric carrier for dispersion of the drug of interest. In addition to the increased drug release rate, solid dispersions should have proper mechanical attributes in order to be successfully formulated in the final solid dosage form such as tablet. Therefore, several pharmaceutical grade polymers have been selected for development of BCS Class II drug carvedilol (CARV) solid dispersions. They were compared based on behavior in supercritical CO2 and affinity towards CARV calculated from the miscibility analysis. By utilization of the supercritical CO2 assisted method, solid dispersions of CARV with the selected (co)polymers (polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), Soluplus® and Eudragit®) were obtained. Properties of the prepared CARV-polymer dispersions were observed by the polarizing and scanning electron microscopy and analyzed by differential scanning calorimetry and Fourier transform infrared spectroscopy. CARV was additionally characterized by X-ray powder diffraction. Furthermore, in vitro dissolution studies and dynamic compaction analysis were performed on the selected samples of solid dispersions. Among the studied polymers, PVP and HPMC have been identified as polymers with the highest affinity towards CARV, based on the calculated δp values. This has been also confirmed with the highest dissolution efficiency of CARV-PVP and CARV-HPMC solid dispersions. Solid state characterization indicated that CARV was dispersed either molecularly, or in the amorphous form, depending on interactions with each polymer. Determination of CARV-PVP and CARV-HPMC mechanical properties revealed that CARV-PVP solid dispersion has superior compactibility and tabletability. Therefore, CARV-PVP solid dispersion has been highlighted as the most appropriate for the further development of tablets as the final dosage form. Presented study provides an example for efficient approach for development of poorly soluble drug solid dispersion with satisfactory tableting properties.

Assessing the potential of solid dispersions to improve dissolution rate and bioavailability of valsartan: In vitro-in silico approach.

This study aimed to improve dissolution rate of valsartan in an acidic environment and consequently its oral bioavailability by solid dispersion formulation. Valsartan was selected as a model drug due to its low oral bioavailability (~23%) caused by poor solubility of this drug in the low pH region of gastrointestinal tract (GIT) and presence of absorption window in the upper part of GIT. Solid dispersions were prepared by solvent evaporation method with Eudragit® E100, Soluplus® or polyvinylpyrrolidone K25 (PVP K25) in drug:polymer weight ratios of 1:1, 1:2, 1:4 and 1:6 and further subjected to solid-state characterization and in vitro drug dissolution testing in 0.1 M HCl. The expected drug plasma concentration vs. time profiles after oral administration of the selected solid dispersion formulations were predicted using physiologically-based in silico modeling. Fast and complete dissolution of valsartan, with >80% of dissolved drug within the first 10 min of testing, was observed only from solid dispersions prepared with Eudragit® E100 in drug:polymer ratios of 1:2, 1:4 and 1:6. In all other samples, valsartan dissolution was slow and incomplete. Solid-state characterization showed amorphous nature of both pure drug and solid dispersion samples, as well as favourable intermolecular interactions between valsartan and polymers over interactions between drug molecules. The constructed in silico model predicted >40% of increase in valsartan bioavailability, Cmax and AUC values from selected solid dispersion formulations compared to conventional solid oral dosage form such as IR capsules. Based on the results of the in vitro-in silico study, formulation of solid dispersions of valsartan with Eudragit® E100 polymer can be considered as a promising approach for improving valsartan bioavailability.

Development of ternary solid dispersions with hydrophilic polymer and surface adsorbent for improving dissolution rate of carbamazepine.

In this study solid dispersions of carbamazepine in the hydrophilic Kollidon® VA64 polymer, adsorbed onto Neusilin® UFL2 adsorption carrier have been employed to improve carbamazepine dissolution rate. In order to evaluate effects of changing in the proportions of all solid dispersion components on carbamazepine dissolution rate, D-optimal mixture experimental design was used in the formulation development. From all prepared solid dispersion formulations, significantly faster carbamazepine dissolution was observed compared to pure drug. Ternary solid dispersions containing carbamazepine, Kollidon® VA64 and Neusilin® UFL2 showed superior dissolution performances over binary ones, containing only carbamazepine and Neusilin® UFL2. Proportion of Kollidon® VA64 showed the most profound effect on the amount of carbamazepine dissolved after 10 and 30 min, whereby these parameters increase upon increasing in Kollidon® VA64 concentrations up to the middle values in the studied range of Kollidon® VA64 concentrations. Physicochemical characterization of the selected samples using differential scanning calorimetry, FT-IR spectroscopy, powder X-ray diffraction and polarizing light microscopy showed polymorphic transition of carbamazepine from more thermodynamically stable monoclinic form (form III) to less thermodynamically stable triclinic form (form I) in the case of ternary, but not of binary solid dispersion formulations. This polymorphic transition can be one of the factors responsible for improving of carbamazepine dissolution rate from studied solid dispersions. Ternary solid dispersions prepared with Kollidon® VA64 hydrophilic polymer and Neusilin® UFL2 adsorption carrier resulted in significantly improvement of carbamazepine dissolution rate, but formation of metastable polymorphic form of carbamazepine requires particular care to be taken in ensuring product long term stability.

Optimization of formulation and process parameters for the production of carvedilol nanosuspension by wet media milling.

The aim of this study is to develop nanosuspension of carvedilol (CRV) by wet media milling. Concentration of polymeric stabilizer (hydroxypropyl cellulose-HPC-SL), milling speed and size of milling beads were identified as critical formulation and process parameters and their effect on CRV particle size after 60 min of milling was assessed using a Box-Behnken experimental design. Optimized nanosuspension was solidified using spray drying and freeze drying and subjected to solid state characterization. Low stabilizer concentration (10%), low milling speed (300 rpm) with small milling beads (0.1 mm) were found as optimal milling conditions. Crystal lattice simulation identified potential slip plane within CRV crystals, where fractures are the most likely to occur. Calculated mechanical properties of CRV crystal indicates that low energy stress is sufficient to initiate fracture, if applied in the correct direction, explaining the advantage of using smaller milling beads. Only spray dried nanosuspension redispersed to original nanoparticles, while particle agglomeration during freeze drying prevented sample redispersion. Wet milling and spray drying did not induce polymorphic transition of CRV, while there is indication of polymorphic transition during freeze drying, making spray drying as the preferred solidification method.

In vitro and in vivo investigation of taste-masking effectiveness of Eudragit E PO as drug particle coating agent in orally disintegrating tablets.

CONTEXT: Considering that bitter taste of drugs incorporated in orally disintegrating tablets (ODTs) can be the main reason for avoiding drug therapy, it is of the utmost importance to achieve successful taste-masking. The evaluation of taste-masking effectiveness is still a major challenge. OBJECTIVE: The objective of this study was to mask bitter taste of the selected model drugs by drug particle coating with Eudragit® E PO, as well as to evaluate taste-masking effectiveness of prepared ODTs using compendial dissolution testing, dissolution in the small-volume shake-flask assembly and trained human taste panel. MATERIALS AND METHODS: Model drugs were coated in fluidized bed. Disintequik™ ODT was used as a novel co-processed excipient for ODT preparation. Selected formulations were investigated in vitro and in vivo using techniques for taste-masking assessment. RESULTS AND DISCUSSION: Significantly slower drug dissolution was observed from tablets with coated drug particles during the first 3 min of investigation. Results of in vivo taste-masking assessment demonstrated significant improvement in drug bitterness suppression in formulations with coated drug. Strong correlation between the results of drug dissolution in the small-volume shake-flask assembly and in vivo evaluation data was established (R ≥ 0.970). CONCLUSION: Drug particle coating with Eudragit® E PO can be a suitable approach for bitter taste-masking. Strong correlation between in vivo and in vitro results implicate that small-volume dissolution method may be used as surrogate for human panel taste-masking assessment, in the case of physical taste-masking approach application.

Dissolution rate enhancement and physicochemical characterization of carbamazepine-poloxamer solid dispersions.

This study investigates the potential of poloxamers as solid dispersions (SDs) carriers in improving the dissolution rate of a poorly soluble drug, carbamazepine (CBZ). Solid dispersions were prepared with poloxamer 188 (P188) and poloxamer 407 (P407) by melting method in different drug:carrier ratios (1:1, 1:2 and 1:3). Prepared samples were characterized using differential scanning calorimetry (DSC), hot-stage polarized light microscopy (HSM), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR) to investigate drug physical state within the SDs matrix, possible polymorphic transitions and drug-polymer interactions. The interactions between CBZ molecules and polymeric chains were also evaluated using molecular dynamics simulation (MDS) technique. The most thermodynamically stable polymorphic form III of CBZ was present in all SDs, regardless of the type of poloxamer and drug-to-carrier ratio. The absence of drug-polymer interactions was observed by FT-IR analysis and additionally confirmed by MDS. Formation of persistent hydrogen bond between two CBZ molecules, observed by MDS indicate high tendency of CBZ molecules to aggregate and form crystalline phase within dispersion. P188 exhibit higher efficiency in increasing CBZ dissolution rate due to its more pronounced hydrophilic properties, while increasing poloxamers concentration resulted in decreasing drug release rate, as a consequence of their thermoreversible gelation.

Combined application of mixture experimental design and artificial neural networks in the solid dispersion development.

This study for the first time demonstrates combined application of mixture experimental design and artificial neural networks (ANNs) in the solid dispersions (SDs) development. Ternary carbamazepine-Soluplus®-poloxamer 188 SDs were prepared by solvent casting method to improve carbamazepine dissolution rate. The influence of the composition of prepared SDs on carbamazepine dissolution rate was evaluated using d-optimal mixture experimental design and multilayer perceptron ANNs. Physicochemical characterization proved the presence of the most stable carbamazepine polymorph III within the SD matrix. Ternary carbamazepine-Soluplus®-poloxamer 188 SDs significantly improved carbamazepine dissolution rate compared to pure drug. Models developed by ANNs and mixture experimental design well described the relationship between proportions of SD components and percentage of carbamazepine released after 10 (Q10) and 20 (Q20) min, wherein ANN model exhibit better predictability on test data set. Proportions of carbamazepine and poloxamer 188 exhibited the highest influence on carbamazepine release rate. The highest carbamazepine release rate was observed for SDs with the lowest proportions of carbamazepine and the highest proportions of poloxamer 188. ANNs and mixture experimental design can be used as powerful data modeling tools in the systematic development of SDs. Taking into account advantages and disadvantages of both techniques, their combined application should be encouraged.

Influence of hydrophilic polymers on the complexation of carbamazepine with hydroxypropyl-ß-cyclodextrin.

In this study binary carbamazepine-hydroxypropyl-ß-cyclodextrin, as well as ternary carbamazepine-hydroxypropyl-ß-cyclodextrin-hydrophilic polymer systems were used to improve dissolution rate of carbamazepine. It has been shown that addition of hydrophilic polymers (Soluplus® and two types of hydroxypropyl methylcellulose-Metolose® 90SH-100 and Metolose® 65SH-1500) significantly increased solubilization capacity of hydroxypropyl-ß-cyclodextrin for carbamazepine. Evaluation of carbamazepine-hydroxypropyl-ß-cyclodextrin-hydrophilic polymer interactions using molecular modeling techniques showed interactions between carbamazepine, which dissociates from inclusion complexes and hydroxypropyl methylcellulose that can prevent crystallization of dissolved carbamazepine. These results can contribute to better understanding of drug-cyclodextrin-hydrophilic polymer interactions which are still not well understood. After evaluation of carbamazepine solubilization with hydroxypropyl-ß-cyclodextrin and hydrophilic polymers, both binary carbamazepine-hydroxypropyl-ß-cyclodextrin and ternary carbamazepine-hydroxypropyl-ß-cyclodextrin-hydrophilic polymer systems were prepared by spray drying. The results of solid state characterization methods showed amorphous nature of carbamazepine in all spray dried systems, which together with the results of molecular modeling techniques indicates inclusion complex formation. Carbamazepine dissolution rate was significantly improved from spray dried formulations compared to pure drug. Binary carbamazepine-hydroxypropyl-ß-cyclodextrin and ternary carbamazepine-hydroxypropyl-ß-cyclodextrin-Soluplus® systems exhibited the fastest carbamazepine release, wherein the entire amount of carbamazepine was released during first 5 min.