Drug-polymer Miscibility Research Articles

Combining ion-pair strategy and percutaneous permeation enhancers to develop sustained-release paliperidone patch

In this study, a sustained-release paliperidone (PAL) patch was developed using a combination of ion-pair strategy and percutaneous permeation enhancers (PPEs). The ion-pair strategy was used to improve drug-adhesive miscibility and control drug release. PPEs were used to break SC barrier function to facilitate drug skin permeation. The in vitro skin permeation experiments using single-factor experiments and Box-Behnken design gave the optimized formulation, a 55 μm adhesive thickness patch with 7 % (w/w) PAL-LA (Lauric acid), 9.7 % (w/w) Plurol® Oleique CC 497 (POCC). Moreover, the pharmacokinetic study confirmed its potential in sustained-release transdermal patch with longer MRT0-t (18.35 ± 3.11 h) and higher BA (63.14 %) than the gavage group (Cmax = 6.64 ± 2.61 μg/mL, MRT0-t = 2.88 ± 1.06 h, BA = 45.70 %) without significant increasing Cmax. The mechanism study revealed that forming ion-pairs effectively modulated drug’s physicochemical properties and doubly ionic H-bond strength to improve drug miscibility in patches. To summarize, a sustained-release patch of PAL was successfully developed, which provided a strategy for sustained-release patches with good drug-polymer miscibility, drug controlled-release, and feasible drug utilization features.

An Advanced Twin-Screw Granulation Technology: The use of Non-Volatile Solvents with High Solubilizing Capacity

PurposeTwin-screw wet granulation (TSWG) is a manufacturing process that offers several advantages for the processing of water-insoluble active pharmaceutical ingredients (APIs) and has been used for increasing the solubility and dissolution rates. Here we introduce a novel TSWG approach with reduced downstream processing steps by using non-volatile solvents as granulating binders.MethodsHerein, TSWG was carried out using Transcutol a non-volatile protic solvent as a granulating binder and dissolution enhancer of ibuprofen (IBU) blends with cellulose polymer grades (Pharmacoat® 603, Affinisol™, and AQOAT®).ResultsThe physicochemical characterisation of the produced granules showed excellent powder flow and the complete transformation of IBU into the amorphous state. Dissolution studies presented immediate release rates for all IBU formulations due to the high drug-polymer miscibility and the Transcutol solubilising capacity.ConclusionsOverall, the study demonstrated an innovative approach for the development of extruded granules by processing water-insoluble APIs with non-volatile solvents for enhanced dissolution rates at high drug loadings.Graphical

A review on amorphous solid dispersions for improving physical stability and dissolution: Role of polymers

Amorphous solid dispersion (ASD) has been a successful strategy to improve solubility and dissolution rate of poorly soluble drugs. ASD improve the solubility and dissolution of drugs by existing as separate molecules in a polymer matrix. The stability of amorphous solid dispersions is dependent on thermodynamic, kinetic and environment factors. Thermodynamic factors include drug-polymer miscibility and solubility. Kinetic factors include glass transition temperatures, molecular mobility, drug-polymer interactions. Environment factors indirectly affect the stability of ASD by influencing the thermodynamic and kinetic factors. The focus of this review is to discuss the role of polymer in influencing the thermodynamic and kinetic stability of ASD.

Multivariate Analysis of Solubility Parameters for Drug-Polymer Miscibility Assessment in Preparing Raloxifene Hydrochloride Amorphous Solid Dispersions.

The success of obtaining solid dispersions for solubility improvement invariably depends on the miscibility of the drug and polymeric carriers. This study aimed to categorize and select polymeric carriers via the classical group contribution method using the multivariate analysis of the calculated solubility parameter of RX-HCl. The total, partial, and derivate parameters for RX-HCl were calculated. The data were compared with the results of excipients (N = 36), and a hierarchical clustering analysis was further performed. Solid dispersions of selected polymers in different drug loads were produced using solvent casting and characterized via X-ray diffraction, infrared spectroscopy and scanning electron microscopy. RX-HCl presented a Hansen solubility parameter (HSP) of 23.52 MPa1/2. The exploratory analysis of HSP and relative energy difference (RED) elicited a classification for miscible (n = 11), partially miscible (n = 15), and immiscible (n = 10) combinations. The experimental validation followed by a principal component regression exhibited a significant correlation between the crystallinity reduction and calculated parameters, whereas the spectroscopic evaluation highlighted the hydrogen-bonding contribution towards amorphization. The systematic approach presented a high discrimination ability, contributing to optimal excipient selection for the obtention of solid solutions of RX-HCl.

Synergistic effect of polymers in stabilizing amorphous pretomanid through high drug loaded amorphous solid dispersion.

Pretomanid (PTM), an oral antibiotic used in the treatment of adults with pulmonary extensively drug-resistant, nonresponsive multidrug-resistant tuberculosis (MDR-TB). It is a poor glass former, that shows high recrystallization tendency from the amorphous and supersaturated state, resulting in low aqueous solubility and suboptimal absorption through the gastrointestinal tract. The present investigation aimed to develop high drug loaded ternary amorphous solid dispersions (ASDs) of PTM with improved stability and enhanced biopharmaceutical performance by utilizing a combination of polymers. The polymers were comprehensively screened based on drug-polymer miscibility and saturation solubility analysis. A combination of Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS-HF) and Polyvinylpyrrolidone K-30 (PVP K-30) showed synergism in drug-polymer miscibility as evidenced through pronounced depression in the melting endotherm of PTM. The Powder X-ray Diffraction (P-XRD) diffractograms of 30% w/w PTM loaded ternary ASDs displayed the halo pattern, contrary to the binary ASDs. Drug-polymer interactions (hydrophobic forces) involved between PTM and polymers were detected through Fourier Transform Infrared Spectroscopy (FT-IR) and Nuclear Magnetic Resonance Spectroscopy (13C-NMR) which contributed to the synergistic enhancement in solubility and dissolution of ternary ASDs with sustained release over 12h. Ternary ASDs demonstrated better in-vivo performance compared to the binary ASDs, showing a 4.63-fold increase in maximum plasma concentration. All ASDs remained stable and resisted phase separation during short-term stability studies for 3 months at ambient conditions. It was concluded that the hydrophobic and hydrophilic polymeric combination (HPMCAS-HF and PVP K-30, respectively) effectively prevented the crystallization and ensured sustained drug release with improved in-vivo absorption of PTM.

Navigating the Solution to Drug Formulation Problems at Research and Development Stages by Amorphous Solid Dispersion Technology.

Amorphous Solid Dispersions (ASDs) have indeed revolutionized the pharmaceutical industry, particularly in drug solubility enhancement. The amorphous state of a drug, which is a highenergy metastable state, can lead to an increase in the apparent solubility of the drug. This is due to the absence of a long-range molecular order, which results in higher molecular mobility and free volume, and consequently, higher solubility. The success of ASD preparation depends on the selection of appropriate excipients, particularly polymers that play a crucial role in drug solubility and physical stability. However, ASDs face challenges due to their thermodynamic instability or tendency to recrystallize. Measuring the crystallinity of the active pharmaceutical ingredient (API) and drug solubility is a complex process that requires a thorough understanding of drug-polymer miscibility and molecular interactions. Therefore, it is important to monitor drug solids closely during preparation, storage, and application. Techniques such as solid-state nuclear magnetic resonance (ssNMR), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), Raman spectroscopy, and dielectric spectroscopy have been successful in understanding the mechanism of drug crystallization. In addition, the continuous downstream processing of drug-loaded ASDs has introduced new automated methods for consistent ASD production. Advanced techniques such as hot melt extrusion, KinetiSol, electro spraying, and electrospinning have gained popularity. This review provides a comprehensive overview of Amorphous Solid Dispersions (ASDs) for oral drug delivery. It highlights the critical challenges faced during formulation, the impact of manufacturing variables, theoretical aspects of drug-polymer interaction, and factors related to drug-polymer miscibility. ASDs have been recognized as a promising strategy to improve the oral bioavailability of poorly water-soluble drugs. However, the successful development of an ASD-based drug product is not straightforward due to the complexity of the ASD systems. The formulation and process parameters can significantly influence the performance of the final product. Understanding the interactions between the drug and polymer in ASDs is crucial for predicting their stability and performance.

A multifaceted approach for grading of polymers for the development of stable amorphous solid dispersion of Riluzole

The current work involves grading three widely used polymers for preparing a kinetically and thermodynamically stable amorphous solid dispersion (ASD) of a neuroprotective drug Riluzole (RLZ) by evaluating the drug-polymer interactions. Polymers were screened based on their chemical interaction with RLZ and their ability to inhibit the crystallization of the drug. Detailed computational studies were performed to quantify the non-covalent interactions between RLZ and the modelled structures of polymers; polyacrylic acid (PAA), polyvinylpyrrolidone vinyl acetate (PVP VA), and hydroxypropyl methyl cellulose acetate succinate (HPMC AS) for calculating the interaction energies of drug-polymer complexes. Experimental characterization of drug-polymer complexes through analytical techniques further validated the formation of the drug-polymer complexes. The results indicated that RLZ interacts with the polymers in the order PAA > PVP VA > HPMC AS, giving an insight into the stability of drug-polymer complexes. In vitro dissolution study also showed higher dissolution profile of RLZ with PAA. Further, the drug-polymer miscibility was determined by employing Flory-Huggins theory and stability in accordance with Gibbs free energy of mixing and phase diagram. This work presented a multi-technique approach for the grading of polymers in search of a stable ASD of the poorly water-soluble drug RLZ.

Investigation of drug-polymer miscibility and design of ternary solid dispersions for oral bioavailability enhancement by Hot Melt Extrusion

The present investigation aimed to enhance the oral bioavailability of the poorly water-s Glibenclamide (GLB) using amorphous solid dispersions (ASD) with various polymers. The drug-polymer miscibility was predicted using in-silico molecular dynamics simulation, Hansen solubility parameter, Flory-Huggins theory, and Gibb’s free energy calculation. To enhance the solubility further, the effervescence amorphous solid dispersions (ESD) technique was included. The solid dispersions (SDs) were initially prepared using the solvent evaporation method. The polymers that enhanced the solubility were optimized by the Design of Experiments (DoE) approach and Hot Melt Extruder (HME) technique. The optimized formulation were subjected to various solid and liquid state characterizations. The XRD and DSC study confirmed conversion into the amorphous form, and hydrogen bonding between the drug and polymer was confirmed by FTIR and 1H NMR. The morphology was assessed by SEM study. The optimized formulation showed enhanced solubility and dissolution data. The optimized formulation remained stable at the accelerated conditions for six months. The optimized formulation subjected to the pre-clinical pharmacokinetic and pharmacodynamics study showed a better pharmacokinetics profile of the drug and enhanced pharmacological activity. Introducing the effervescent technique to the conventional ASD technique helped to enhance the physicochemical properties with improved pharmacological action.

Drug-Polymer Miscibility and Interaction Study as a Preliminary Step in Amorphous Solid Dispersion Development: Comparison of Theoretical and Experimental Data

Drug-Polymer Miscibility and Interaction Study as a Preliminary Step in Amorphous Solid Dispersion Development: Comparison of Theoretical and Experimental Data

Drug-Polymer Miscibility and the Overlap Concentration (C*) as Measured by Rheology: Variation of Polymer Structure.

Amorphous solid dispersions (ASDs), wherein a drug is molecularly dispersed in a polymer, can improve physical stability and oral bioavailability of poorly soluble drugs. Risk of drug crystallization is usually averted using high polymer concentrations. However, we demonstrated recently that the overlap concentration, C*, of polymer in drug melt is the minimum polymer concentration required to maintain drug in the amorphous state following rapid quench. This conclusion was confirmed for several drugs mixed with poly(vinylpyrrolidone) (PVP). Here we assess the solid-state stability of ASDs formulated with a variety of polymers and drugs and at various polymer concentrations (C) and molecular weights (MWs). We further test the hypothesis that degree of drug crystallization decreases with increasing C/C* and vanishes when C>C*, where C* depends on polymer MW and strength of drug-polymer interaction. We test our hypothesis with ASDs consisting of ketoconazole admixed with polyacrylic acid, polymethacrylic acid and poly (methacrylic acid-co-ethyl acrylate); and felodipine admixed with PVP and poly (vinylpyrrolidone-co-vinyl acetate). Values of C* for polymers in molten drug are rheologically determined. Crystallization behavior is assessed by measuring enthalpy of fusion, ΔHf and by X-ray diffraction. We confirm that ΔHf/ΔHf, C = 0 = f(C/C∗), and essentially no crystallization occurs when C>C*. Our findings will aid researchers in designing or selecting appropriate polymers to inhibit crystallization of poorly soluble drugs. This research also suggests that C* as determined by rheology can be used to compare drug-polymer interactions for similar molecular weight polymers.

Corroborating various material-sparing techniques with hot melt extrusion for the preparation of triclabendazole amorphous solid dispersions

Amorphous solid dispersions (ASD) are one of the most adopted technologies for improving the solubility of novel molecules. Formulation of ASDs using solvent free methods such as hot melt extrusion (HME) has been in the spotlight off-lately. However, early-stage formulation development is tricky and a difficult bridge to pass due to limited drug availability. Material-sparing techniques (theoretical & practical) have been used for selecting suitable polymeric carriers for formulating ASDs. However, these techniques have limitations in predicting the effect of process parameters. The objective of this study is to use both theoretical and practical material-sparing techniques to optimize a polymer for the developing Triclabendazole (TBZ) ASDs. Initial screening by theoretical approaches suggested that TBZ is highly miscible with Kollidon®VA64 (VA64) and poorly miscible with Parteck®MXP (PVA). However, results from ASDs prepared using SCFe were opposite to these predictions. ASDs prepared using either technique and both VA64 and PVA showed >200x increase in solubility. Each formulation released >85% of drug in less than 15 mins. Although the thermodynamic phase diagram suggested that VA64 was the ideal polymer for TBZ-ASDs, it has certain limitations in factoring the different elements during melt-processing and hence, practical approaches like SCFe could help in predicting the drug-polymer miscibility for HME processing.

Selection of appropriate dapsone and poly(1-vinylpyrrolidone-co-vinyl acetate) ratios for the preparation of amorphous solid dispersions

Drug-polymer miscibility is a critical requirement for the efficient design and development of amorphous solid dispersions. The objective of the current study was to determine the miscibility between dapsone (DAP) and poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP-VA) through theoretical and experimental approaches, including the use of a thermodynamic phase diagram and Gibbs free energy of mixing. In the theoretical study, the difference in the solubility parameter between the DAP and PVP-VA was 2.74, the interaction parameter was 0.50, and the distance between the drug and polymer in the Bagley plot was 2.60. Hence, all these theoretical parameters favour the miscibility between DAP and PVP-VA. Melting point depression study (through thermal analysis) and Flory-Huggins theory were utilized for the practical determination of drug-polymer miscibility, where the interaction parameter was positive, suggesting limited miscibility. The obtained thermodynamic phase diagram and Gibbs free energy of mixing plot can provide an indication for the selection of appropriate drug-polymer ratios in stable and metastable zones and the optimum processing temperature required for the preparation of amorphous solid dispersions.

Downstream processing of amorphous solid dispersions into tablets

Amorphous solid dispersions have gained tremendous attention as a commercially viable solubility enhancement technique for poorly water-soluble drugs. However, poor drug loading associated with poor drug-polymer miscibility is a major challenge in the downstream processing of ASDs. While many downstream techniques are available for converting ASDs into final dosage forms, oral solids remain the most commercially viable. The type of excipients used in the conversion of ASDs into tablets are very similar to the excipients used in conventional tablets. For example, the binders used in conventional tablets are widely used as polymeric carriers in case of ASDs. The physical properties of ASDs manufactured using spray drying or hot melt extrusion pose major challenge in converting ASDs into oral tablets. The current review focuses on various challenges associated with converting ASDs into tablets and provide a comprehensive review on various excipients used in manufacturing tablets using ASDs.

Challenges, current status and emerging strategies in the development of rapidly dissolving FDM 3D-printed tablets: An overview and commentary.

Since the approval of a 3D-printed tablet by the FDA in 2015 for marketing, there has been a great interest in 3D printing in the pharmaceutical field for the development of personalized and on-demand medications. Among various 3D printing methods explored for the development of oral solid dosage form like tablet, the fused deposition modeling (FDM) 3D-printing, where the drug-polymer mixtures are first converted into filaments by hot melt extrusion (HME) and then the filaments are printed into tablets using 3D printers by applying computer-aided design principles, has emerged as the most attractive option. However, no FDM 3D-printed tablets have yet been marketed as the technology faces many challenges, such as limited availability of pharmaceutical-grade polymers that can be printed into tablets, low drug-polymer miscibility, the need for high temperature for HME and 3D-printing, and slow drug release rates from tablets. These challenges are discussed in this article with a special focus on drug release rates since FDM 3D-printing usually leads to the preparation of slow-release tablets while the rapid release from dosage forms is often desired for optimal therapeutic outcomes of new drug candidates. Pros and cons of various strategies for the development of rapidly dissolving FDM 3D-printed tablets reported in the literature are reviewed. Finally, two case studies on emerging strategies for the development of rapidly dissolving FDM 3D-printed tablets are presented, where one outlines a systematic approach for formulating rapidly dissolving tablets, and the other describes a novel strategy to increase dissolution rates of drugs from FDM 3D-printed tablets, which at the same time can also increase drug-polymer miscibility and printability of tablets and lower processing temperatures. Thus, this overview and commentary discusses various issues involving the formulation of rapidly dissolving FDM 3D-printed tablets and provides guidance for the development of commercially viable products.

High drug-loading and controlled-release hydroxyphenyl-polyacrylate adhesive for transdermal patch.

Long-acting transdermal drug delivery system (TDDS) requires high drug-loading and drug controlled-release. To simultaneously improve drug-polymer miscibility and realize drug controlled-release, this work aimed to develop a new pressure sensitive adhesive modified with hydroxyphenyl (HP-PSA) by introducing doubly ionic H-bond into drug-PSA interaction. Eight model drugs divided into R3N, R2NH and no N type were chosen to understand the characteristics of the HP-PSA and inner mechanism. The results showed that the doubly ionic H-bond between R3N and R2NH type drugs and HP-PSA, differing from the ionic bond and neutral H-bond, was a reversible and relatively strong interaction. It could significantly enhance their drug-loading by 1.5 to 7 times and control drug release rate to its 1/5 to 1/2 without altering its total release properties, outperforming the commercial Duro-Tak® 87-2510 and Duro-Tak® 87-2852 adhesives. According to the pharmacokinetics results, the high drug-loading patches based on HP-PSA achieved a sustainable plasma drug concentration avoiding burst release, and over 2 times area under concentration-time curve (AUC) as well as 6 times mean residence time (MRT) revealed its potential to realize long-acting drug delivery. Additionally, its safety and mechanical features were satisfied. The mechanism study showed that the repulsion of the ionic drugs in HP-PSA increased drug-loading, and the relatively strong interaction could also control drug release. The incomplete H-bond transfer determined its reversibility, thus making the drug release percentage up to that of non-functional PSA. In conclusion, the high drug-loading efficiency and drug controlled-release capacity of HP-PSA, as well as its unique interaction, would contribute to the development of TDDS. Moreover, the construction of the doubly ionic H-bond would provide further inspiration for various drug delivery systems in the non-polar environment.

Improving drug release rate, drug-polymer miscibility, printability and processability of FDM 3D-printed tablets by weak acid-base interaction

Slow drug release, low drug-polymer miscibility, poor printability of polymers used, and high processing temperature are major challenges in developing FDM 3D-printed tablets. These challenges were addressed in this investigation by having a model basic drug, haloperidol (mp: 151.5 °C), interact with a weak acid, malic acid (mp: 130 °C), during the melt extrusion of formulations into filaments used for 3D-printing. Malic acid was selected as it was previously reported that it did not form any crystalline salt with haloperidol but its addition to aqueous media could greatly increase the solubility of haloperidol from ∼ 1 µg/mL to > 1 g per mL of water by acid-base supersolubilization. Concentrated solutions of haloperidol-malic acid mixtures produced amorphous materials upon drying. It has been observed in the present investigation that similar interaction between haloperidol and malic acid may also occur in the absence of water. Upon heating, haloperidol-malic acid mixtures at 1:1 and 1:2 molar ratios turned amorphous starting at ∼ 50 °C, which is much below the melting point of either component. When Kollidon® VA64, a brittle and non-printable polymer, was used as the polymeric carrier, the acid-base interaction greatly reduced the melt viscosity of haloperidol-malic acid-Kollidon® VA64 ternary mixtures. Consequently, melt extrusion of filaments and printing of tablets using such mixtures could be performed at much lower temperatures than those with haloperidol-Kollidon® VA64 binary mixtures. The filaments containing 15 % and 30 % haloperidol along with malic acid and Kollidon® VA64 could be printed into tablets at relatively low temperatures of 125 and 100 °C, respectively, thus making Kollidon® VA64 not only printable but also doing so at low temperatures. Up to 50 % w/w drug load in filaments was achieved without any crystallization of haloperidol or malic acid. Drug release at pH 2 and 6.8 from printed tablets with 100 % infill was 80 % in < 30 min. Thus, the acid-base interaction can successfully resolve multiple development challenges encountered with FDM 3D-printed tablets.

The role of hydrophilic/hydrophobic group ratio of polyvinyl alcohol on the miscibility of amlodipine in orodispersible films: From molecular mechanism study to product attributes

The miscibility of the therapeutic drug in the polymer matrix is the key to the successful design and development of orodispersible films (ODFs). In the present study, four hydrolyzed polyvinyl alcohols (PVAs) with identical polymerization degree were investigated as carriers for Amlodipine (AML) ODFs systematically. The drug-polymer miscibility and the intermolecular interaction were investigated by Flory-Huggins theory, Gordon-Taylor theory, molecular simulation, FTIR, Raman and 1H NMR. The product attributes of ODFs were also studied. A pharmacokinetic study in rats was then conducted using the film product of PVA5-72, the best performer tested. The results revealed that the drug-polymer miscibility decreased linearly with the increase of hydrolyzed degree of PVA. Hydrogen bonds formed between the drug and the hydrophilic and hydrophobic groups of PVAs were the main intermolecular interaction that caused the differences in drug-polymer miscibility. Furthermore, drug-polymer interaction influenced the product attributes of ODFs, including dissolution profile, mechanical properties and physical stability. The pharmacokinetic study showed the ODFs disintegrated rapidly, and the amorphous AML dissolved and absorbed in the gastrointestinal tract, which was comparable to the commercial product. The research offered a foundation for development scientists in designing and formulating PVA films.

Personalised paediatric chewable Ibuprofen tablets fabricated using 3D micro-extrusion printing technology

Three-dimensional (3D) printing is becoming an attractive technology for the design and development of personalized paediatric dosage forms with improved palatability. In this work micro-extrusion based printing was implemented for the fabrication of chewable paediatric ibuprofen (IBU) tablets by assessing a range of front runner polymers in taste masking. Due to the drug-polymer miscibility and the IBU plasticization effect, micro-extrusion was proved to be an ideal technology for processing the drug/polymer powder blends for the printing of paediatric dosage forms. The printed tablets presented high printing quality with reproducible layer thickness and a smooth surface. Due to the drug-polymer interactions induced during printing processing, IBU was found to form a glass solution confirmed by differential calorimetry (DSC) while H-bonding interactions were identified by confocal Raman mapping. IBU was also found to be uniformly distributed within the polymer matrices at molecular level. The tablet palatability was assessed by panellists and revealed excellent taste masking of the IBU’s bitter taste. Overall micro-extrusion demonstrated promising processing capabilities of powder blends for rapid printing and development of personalised dosage forms.

Investigation of tadalafil molecular arrangement in solid dispersions using inverse gas chromatography and Raman mapping

The aim of this study was to investigate the molecular structures of tadalafil solid dispersions prepared by different techniques and further to relate them to surface free energy information indicating the final amorphousness of the product. Thus, we tried to complement the existing knowledge of solid dispersion formation. Poorly water-soluble tadalafil was combined with different polymers, i.e. Kollidon® 12 PF, Kollidon® VA 64 and Soluplus®, to form model systems. To assess the extent of drug-polymer miscibility, we studied model solid dispersion surface energy using inverse gas chromatography and phase micro-structure using confocal Raman microscopy. The selection of the preparation method was found to play a crucial role in the molecular arrangement of the incorporated drug and the polymer in resulting solid dispersion. Our results showed that a lower surface free energy indicated the formation of a more homogeneous solid dispersion. Conversely, a higher surface free energy corresponded to the heterogeneous systems containing tadalafil amorphous clusters that were captured by Raman mapping. Thus, we successfully introduced a novel evaluation approach of the drug molecular arrangement in solid dispersions that is especially useful for examining the miscibility of the components when the conventional characterizing techniques are inconclusive or yield variable results.

Development and Characterization of Eudragit® EPO-Based Solid Dispersion of Rosuvastatin Calcium to Foresee the Impact on Solubility, Dissolution and Antihyperlipidemic Activity.

Poor solubility is the major challenge involved in the formulation development of new chemical entities (NCEs), as more than 40% of NCEs are practically insoluble in water. Solid dispersion (SD) is a promising technology for improving dissolution and, thereby, the bioavailability of poorly soluble drugs. This study investigates the influence of a pH-sensitive acrylate polymer, EPO, on the physicochemical properties of rosuvastatin calcium, an antihyperlipidemic drug. In silico docking was conducted with numerous polymers to predict drug polymer miscibility. The screened-out polymer was used to fabricate the binary SD of RoC in variable ratios using the co-grinding and solvent evaporation methods. The prepared formulations were assessed for physiochemical parameters such as saturation solubility, drug content and in vitro drug release. The optimized formulations were further ruled out using solid-state characterization (FTIR, DSC, XRD and SEM) and in vitro cytotoxicity. The results revealed that all SDs profoundly increased solubility as well as drug release. However, the formulation RSE-2, with a remarkable 71.88-fold increase in solubility, presented 92% of drug release in the initial 5 min. The molecular interaction studied using FTIR, XRD, DSC and SEM analysis evidenced the improvement of in vitro dissolution. The enhancement in solubility of RoC may be important for the modulation of the dyslipidemia response. Therefore, pharmacodynamic activity was conducted for optimized formulations. Our findings suggested an ameliorative effect of RSE-2 in dyslipidemia and its associated complications. Moreover, RSE-2 exhibited nonexistence of cytotoxicity against human liver cell lines. Convincingly, this study demonstrates that SD of RoC can be successfully fabricated by EPO, and have all the characteristics that are favourable for superior dissolution and better therapeutic response to the drug.