Drug-polymer Miscibility Research Articles

Exploration of theoretical and practical evaluation on Kollidon®SR matrix mediated amorphous filament extrusion of norfloxacin by melt extrusion

The selection of an appropriate polymer for the preparation of amorphous solid dispersions via hot-melt extrusion (HME) deals with the study of various solid-state properties of drugs and polymers. Hence, before going to HME, it is necessary to have appropriate knowledge of drug-polymer miscibility, drug-polymer interactions, and Gibb's free energy of mixing for the respective drug-polymer system. In the present work, we evaluated the miscibility and interaction parameters between norfloxacin (NOR) and Kollidon®SR Powder (KSR-P). The solubility parameter approach, based on theoretical calculations, was performed as a preliminary step for the prediction of miscibility between NOR and KSR-P. A theoretical and experimental approach was used as a validation tool using Flory-Huggin's interaction parameter value determined using the melting point depression method. The effect of NOR loading on the interaction parameter was systemically predicted to construct a thermodynamic phase diagram and Gibb's free energy of mixing for the NOR and KSR-P binary systems for the preparation of amorphous filament extrudate. A temperature-composition phase diagram was used to predict the processing temperature at the respective NOR loading to obtain a homogenous amorphous extrudate. Further, the obtained extrudate was evaluated through dimension studies, NOR assay, DSC, XRD, ATR analysis, and release behaviour.

The use of optical differential scanning calorimetry to investigate ibuprofen miscibility in polymeric films for topical drug delivery

Understanding drug miscibility in pharmaceutically relevant systems is essential for the development and optimisation of pharmaceutical dosage forms. This is particularly true for film forming systems which are designed to become supersaturated with drug, following application on the skin surface, whilst maintaining the physical stability of the drug for a suitable period to enhance drug delivery. For such formulations, chemical penetration enhancers as well as the drug are absorbed from the formulation into the skin, making understanding drug delivery from the films challenging. This study investigated the use of an optical differential scanning calorimetry (DSC) to understand drug miscibility in polymeric film forming systems and explain drug transport behaviour from film forming formulations, containing ibuprofen, a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (Eudragit® E, EuE), a copolymer based on ethyl acrylate, methyl methacrylate and methacrylic acid ester with quaternary ammonium groups (Eudragit® RS, EuRS) and a copolymer based on methacrylic acid and methyl methacrylate (Eudragit® S, EuS), with and without the chemical penetration enhancer propylene glycol, across a model membrane. The optical DSC enabled the rapid screening of not only drug-polymer miscibility, but also drug-vehicle miscibility, while considering both the melting-point depression and melting enthalpy of the drug due to the presence of the polymer/polymer-based vehicle, obtained via thermal analysis by structural characterisation (TASC) and DSC analysis, respectively. The results obtained enable the polymers studied to be ranked in the order of EuE > EuRS > EuS, with EuE being more miscible with ibuprofen, and the incorporation of a penetration enhancer in the film forming system formulation was found to increase ibuprofen solubility in EuE- and EuRS- based films. The drug-polymer/vehicle miscibility information obtained via optical DSC provided understanding of drug transport from film forming systems with the higher miscibility of ibuprofen with EuE reducing drug transport through decreasing drug saturation in the film. The higher drug transport from films containing EuRS and EuS could also be linked to drug miscibility with the polymer and showed dependence on ibuprofen loading in the formulation. Overall optical DSC has been demonstrated to be a valuable tool for determining drug-vehicle miscibility for pharmaceutical product development.

Theoretical and experimental validation of praziquantel with different polymers for selection of an appropriate matrix for hot-melt extrusion

The selection of an appropriate matrix for the preparation of amorphous extrudate in hot-melt extrusion (HME) deals with the study of various solid-state properties of drugs and polymers. Therefore, it is necessary to have an appropriate knowledge of drug-polymer miscibility, the interaction between the drug-polymer on mixing, and Gibb's free thermal energy of mixing to screen polymers through thermodynamic phase diagrams, to be suitable amorphous matrix system for HME. Here, we evaluated the possibility of three different polymers, namely, Eudragit®EPO, polyvinyl alcohol (PVA), Kollicoat®IR (KIR) with Praziquantel (PZQ), with proper validation of the Flory-Huggins theory and construction of the phase diagram using the melting point depression approach to determine a suitable matrix for HME. The solubility parameter theoretical calculation approach was used as a preliminary study to validate the miscibility of PZQ with three different polymers. Theoretical and experimental validation studies using the Flory-Huggins interaction parameter value using the melting point depression approach and the effect of PZQ loading on the interaction parameter were systematically validated to predict thermodynamic phase diagrams and Gibbs free energy of mixing for screening these polymers for the preparation of amorphous extrudate. Using the phase diagram, the thermal processing temperature for the HME was determined using a T-φ phase diagram to obtain an appropriate matrix. The obtained extrudates were further validated through physical appearance, microscopic structure, thermal and functional group characterizations, followed by the PZQ assay. Thus, considering the solid-state properties, the processing parameters of HME were selected to obtain stable extrudates and an appropriate matrix for PZQ loading.

Solvent influence on manufacturability, phase behavior and morphology of amorphous solid dispersions prepared via bead coating

Bead coating or fluid-bed coating serves as an auspicious solvent-based amorphous solid dispersion (ASD) manufacturing technique in respect of minimization of potential physical stability issues. However, the impact of solvent selection on the bead coating process and its resulting pellet formulation is, to the best of our knowledge, never investigated before. This study therefore aims to investigate the influence of the solvent on the bead coating process itself (i.e. manufacturability) and on solid-state characteristics of the resulting ASDs coated onto beads. For this purpose, the drug-polymer system felodipine (FEL)-poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) was coated onto microcrystalline cellulose (MCC) beads from acetonitrile (ACN), methanol (MeOH), ethanol (EtOH), acetone (Ac), 2-propanol (PrOH), dichloromethane (DCM) and ethyl acetate (EthAc). A drug loading screening approach with bead coating revealed analogous ability to manufacture high drug-loaded ASDs from the different organic solvents. The results show no correlation with crystallization tendency or with equilibrium solubility of the drug in the different solvents, nor with the solvent-dependent drug-polymer miscibility obtained from film casting experiments. Distinct coating morphologies were however observed for PVP-VA and FEL-PVP-VA ASDs deposited onto beads from the various solvents, which is attributed to differences in solvent evaporation kinetics.

Analytical and Computational Methods for the Determination of Drug-Polymer Solubility and Miscibility.

In the pharmaceutical industry, poorly water-soluble drugs require enabling technologies to increase apparent solubility in the biological environment. Amorphous solid dispersion (ASD) has emerged as an attractive strategy that has been used to market more than 20 oral pharmaceutical products. The amorphous form is inherently unstable and exhibits phase separation and crystallization during shelf life storage. Polymers stabilize the amorphous drug by antiplasticization, reducing molecular mobility, reducing chemical potential of drug, and increasing glass transition temperature in ASD. Here, drug-polymer miscibility is an important contributor to the physical stability of ASDs. The current Review discusses the basics of drug-polymer interactions with the major focus on the methods for the evaluation of solubility and miscibility of the drug in the polymer. Methods for the evaluation of drug-polymer solubility and miscibility have been classified as thermal, spectroscopic, microscopic, solid-liquid equilibrium-based, rheological, and computational methods. Thermal methods have been commonly used to determine the solubility of the drug in the polymer, while other methods provide qualitative information about drug-polymer miscibility. Despite advancements, the majority of these methods are still inadequate to provide the value of drug-polymer miscibility at room temperature. There is still a need for methods that can accurately determine drug-polymer miscibility at pharmaceutically relevant temperatures.

Evaluation of the impact of surfactants on miscibility of griseofulvin in spray dried amorphous solid dispersions

The aim of this contribution is to examine the impact of incorporating surfactants into amorphous solid dispersions on solid state miscibility and aqueous solubility of the antifungal drug griseofulvin. Spray dried amorphous solid dispersions of griseofulvin (GF) and hypromellose acetate succinate (HPMCAS) were prepared by spray drying. Three different surfactants of varying ratios between 1 to 5% were used namely the anionic sodium dodecyl sulfate (SDS), the cationic dodecyletrimethylammonium bromide (DTAB) and the non-ionic pluronic (F127). Flory-Huggins model combined with calculations based on Hoffman's equation were used to calculate miscibility and predicted solubility of the amorphous form. The results showed that the prepared solid dispersions exhibited enhanced drug-polymer miscibility reflected by improved thermodynamics of mixing. The highest miscibility was achieved when DTAB was incorporated by which the drug-polymer miscibility was enhanced by approximately 1.5 times. The tendency to recrystallize was calculated using reduced recrystallization parameter and correlated with the measured saturation solubility showing distinct properties which were dependent on the type of surfactant. Saturated solubility of the solid dispersions was compared with micellar solubility and was found to be significantly affected by the presence of the polymer. The glass transition temperature (Tg) decreased significantly upon the addition of surfactants. However, gravimetric analysis showed that solvent content did not exceed 1% which suggests that the shifted Tg was not related to plasticizing effect of residual solvent. Overall, these results suggest potential role for the surfactants in enhancing solid state miscibility when incorporated into the solid dispersions.

Development of FDM 3D-printed tablets with rapid drug release, high drug-polymer miscibility and reduced printing temperature by applying the acid-base supersolubilization (ABS) principle

Some of the major issues with the development of FDM 3D printed tablets are slow drug release, lack of drug-polymer miscibility, high processing temperature, and poor printability. In this investigation, these issues were addressed by using a novel physicochemical principle called acid-base supersolubilization (ABS) previously developed in our laboratory. The aqueous solubility of a basic drug, haloperidol, was increased to ~300 mg/g of solution by adding glutaric acid, and, upon drying, the concentrated solutions produced amorphous materials. Similar amorphous systems could also be produced by heating haloperidol-glutaric acid mixtures. Filaments for 3D printing were prepared by melt extrusion of formulations containing 15% w/w haloperidol and 10.5% glutaric acid (1:2 M ratio) along with 74.5% polymers, such as Kollidon® VA64 alone or its mixtures with Affinisol™ 15cP. Filaments could be extruded and printed at low temperatures of 115 and 120 °C, respectively. Haloperidol was fully miscible in the formulations because of the acid-base interaction and formed amorphous systems even at higher drug loads. Although filaments of haloperidol-Kollidon® VA64 mixtures by themselves cannot be printed, the printability of formulation improved such that those containing glutaric acid were printable. Drug release rates from the formulations at pH 2 and 6.8 were rapid and complete.

Investigating crystallization tendency, miscibility, and molecular interactions of drug–polymer systems for the development of amorphous solid dispersions

Crystallization tendencies, thermal analysis [i.e. glass transition temperature (T g)], crystallinity, and melting point depression, along with theoretical calculations such as solubility parameter, of five different drugs [i.e. curcumin (CUR), indomethacin (IND), flutamide (FLU), dipyridamole (DIP), and griseofulvin (GRI)] in the absence and presence of four different polymers in various drug–polymer ratios were determined and analyzed. Physical states of the drug in the solid dispersions (SDs) and their stability were characterized by X-ray diffraction and modulated differential scanning calorimetry. Infrared (IR) and Raman were used in selected systems (i.e. CUR, DIP, and GRI systems) to explore the role of drug–polymer interactions in the amorphization of SDs. The crystallization tendencies of pure drugs were categorized as low (CUR, IND), moderate (FLU), and high (DIP, GRI). In the presence of selected polymers, the crystallization tendency of the drugs changed, though a high polymer concentration was required for high crystallization-tendency drugs [i.e. DIP and GRI (>50% w/w)]. Polymers showing a greater effect on the crystallization tendency of drugs were found to have higher drug–polymer miscibility and stronger molecular interactions. Drug–polymer systems selected from the investigation of physical mixtures formed stable amorphous solid dispersions (ASD). Furthermore, the rank order of the crystallization tendency of drug–polymer systems correlated well with those on miscibility and molecular interactions. Those rank orders also correlated well with the stability of prepared/reported SDs. Hence, the developed approach has significant potential to be a rational screening method for the development of amorphous SDs.

3D printing of immediate-release tablets containing olanzapine by filaments extrusion

In this work, hot-melt extrusion (HME) is coupled with fused deposition modeling (FDM) mediated 3D printing to demonstrate additive manufacturing to fabricate immediate release (IR) prototypes of olanzapine with the aim of enhanced solubility using a fast disintegrating polymer (Kollicoat® IR). Drug-polymer solubility and interaction parameters were estimated by Hansen solubility parameters and Hildebrand–Scott equation. The obtained values signified drug–polymer miscibility. The detailed in vitro physicochemical evaluations of the developed filament through HME and its derived 3D printed tablet by FDM technique were assessed thoroughly by several analytical means such as light microscopy, DSC, XRD, FT-IR, SEM, etc. The average disintegration time of this developed 3D printed IR tablet was found to be 63.33 (±3.6) sec complying with the USP limit. Additionally, in vitro dissolution study data revealed almost close correlations and both showed 100% of drug release within 15 min, thus complying with the definition of IR tablet. Thus, this study demonstrates the feasibility of directly using olanzapine-Kollicoat® IR through the HME process without the addition of any plasticizers, organic solvents, etc. and coupling of HME with 3D printing technology allowing prototypes of IR tablet of olanzapine.

Amorphous Solid Dispersions of Felodipine and Nifedipine with Soluplus®: Drug-Polymer Miscibility and Intermolecular Interactions.

The objective of this study was to investigate thermodynamic and kinetic miscibility for two structurally similar model compounds nifedipine (NIF) and felodipine (FEL) when formulated as amorphous solid dispersions (ASDs) with an amphiphilic polymer Soluplus®. Thermodynamic miscibility was studied via melting point depression approach for the two systems. The Flory Huggins theory was used to calculate the interaction parameter and generate the phase diagrams. It was shown that NIF was more miscible in Soluplus® than FEL. The nature of drug polymer interactions was studied by fourier transform infra-red spectroscopy (FTIR) and solid-state nuclear magnetic resonance spectroscopy (ssNMR). The data from spectroscopic analyses showed that both the drugs interacted with Soluplus® through hydrogen bonding interactions. Furthermore, 13C ssNMR data was used to get quantitative estimate of the extent of hydrogen bonding for ASDs samples. Proton relaxation measurements were carried out on ASDs in order to evaluate phase heterogeneity on two different length scales of mixing. The data suggested that better phase homogeneity in NIF:SOL systems especially for lower Soluplus® content ASDs on smaller domains. This could be explained by understanding the extent of hydrogen bonding interactions for these two systems. This study highlights the need to consider thermodynamic and kinetic mixing, when formulating ASDs with the goal of understanding phase mixing between drug and polymer.

Correlationship of Drug-Polymer Miscibility, Molecular Relaxation and Phase Behavior of Dipyridamole Amorphous Solid Dispersions.

In present work, a correlationship among quantitative drug-polymer miscibility, molecular relaxation and phase behavior of the dipyridamole (DPD) amorphous solid dispersions (ASDs), prepared with co-povidone (CP), hydroxypropyl methylcellulose phthalate (HPMC P) and hydroxypropyl methylcellulose acetate succinate (HPMC AS) has been investigated. Miscibility predicted using melting point depression approach for DPD with CP, HPMC P and HPMC AS at 25°C was 0.93% w/w, 0.55% w/w and 0.40% w/w, respectively. Stretched relaxation time (τβ) for DPD ASDs, measured using modulated differential scanning calorimetry (MDSC) at common degree of undercooling, was in the order of DPD- CP>DPD-HPMC P>DPD-HPMC AS ASDs. Phase behavior of 12 months aged (25±5°C and 0% RH) spray dried 60% w/w ASDs was tracked using MDSC. Initial ASD samples had homogeneous phase revealed by single glass transition temperature (Tg) in the MDSC. MDSC study of aged ASDs revealed single-phase DPD-CP ASD, amorphous-amorphous and amorphous-crystalline phase separated DPD-HPMC P and DPD-HPMC AS ASDs, respectively. The results were supported by X-ray micro computed tomography and confocal laser scanning microscopy studies. This study demonstrated a profound influence of drug-polymer miscibility on molecular mobility and phase behavior of ASDs. This knowledge can help in designing "physical stable" ASDs.

In vitro-in silico evaluation of Apremilast solid dispersions prepared via Corotating Twin Screw Extruder

The purpose of this study was to employ the Hot melt extrusion technique (HME) to prepare amorphous solid dispersions (ASDs) of Apremilast, a BCS class IV drug. Drug–polymer miscibility was assessed with solubility parameter and the Flory-Huggins equation. Soluplus® was selected as the carrier and solid dispersions were prepared in 10:90, 30:70 and 50:50 drug: polymer ratios. The study evaluated the influence of drug loading and extrusion temperature on the solid dispersions. The produced solid dispersion were characterized using FTIR, DSC and XRD. Pharmacokinetics of Apremilast following oral delivery of the solid dispersion formulations were predicted in silico using GastroPlus™. The extruder processing temperature had a profound influence on the generation of ASDs. Solid-state characterization exhibited amorphous nature of drug in the solid dispersion samples. The constructed in silico model predicted more than 50% of increase in Apremilast Cmax and AUC values from solid dispersion formulations compared to plain Apremilast. In conclusion, the Apremilast ASDs formulated with Soluplus® showed a significant increase in solubility and may be considered as a favorable approach for enhancing Apremilast oral bioavailability. Stress samples stored at 25 °C/75% RH condition for 10 days showed decrease in dissolution profile for ASDs with 50% and 90% Soluplus® and no change was observed in ASDs with 70% Soluplus®. Based on the conducted studies, an optimum drug: polymer ratio of 30:70 was suggested for Apremilast: Soluplus® ASDs for further development.

In Vitro and In Vivo Behaviors of KinetiSol and Spray-Dried Amorphous Solid Dispersions of a Weakly Basic Drug and Ionic Polymer†.

Oral delivery of poorly water-soluble, weakly basic drugs may be problematic based on the drugs' intrinsic properties. Many drugs in this subset have overcome barriers to delivery following successful formulation as amorphous solid dispersions (ASDs). To process drugs as ASDs, multiple commercially relevant technologies have been developed and become well understood. However, ASD-producing technologies like spray drying and KinetiSol produce ASDs with vastly differing particle characteristics. Ultimately, the objective of this study was to assess whether processing an ASD of identical composition utilizing two different ASD-producing technologies (KinetiSol and spray drying) may impact the oral bioavailability of a weakly basic drug. For this study, we selected a weakly basic drug (Boehringer Ingelheim research compound 639667, BI 667) and processed it with an anionic polymer (hypromellose acetate succinate MMP grade (HPMCAS-MMP)) to evaluate whether the processing technology could modulate drug release in acidic and neutral media. Multiple characterization techniques (specific surface area (SSA), particle size distribution (PSD), scanning electron microscopy (SEM)) were utilized to evaluate the surface characteristics and differences in particles produced by KinetiSol and spray drying. Molecular interactions and drug-polymer miscibility of the processed particles were assessed using Fourier transform infrared spectroscopy and solid-state nuclear magnetic resonance, respectively. In vitro nonsink, pH-shift dissolution in biorelevant media and dissolution/permeation studies were conducted to better understand the release of BI 667 based on processing technology and particle size distribution. Finally, an in vivo male Beagle dog study was conducted to assess the impact of processing technology on oral bioavailability. In this study, we demonstrate that particles produced by KinetiSol have enhanced oral bioavailability compared with spray-dried particles when delivering a weakly basic drug processed with an anionic polymer. The findings of this study demonstrate that by utilizing KinetiSol, drug release may be controlled such that supersaturation in acidic media is inhibited and supersaturation of the drug is designed to occur in neutral media, ultimately enhancing oral bioavailability.

Development of Tizanidine Drug-in-Adhesive Patch: Molecular Mechanism of Permeation Enhancer on Regulating Miscibility and Drug Release by Affecting the Status of Ion-Pair in Polymer Matrix

The objective of this work was to develop a drug-in-adhesive (DIA) patch of TIZ by employing ion-pair and permeation enhancer to increase drug-polymer miscibility and drug release. Special attention was paid on the regulation effect of permeation enhancer on ion-pair status in pressure sensitive adhesives (PSA). Formulation factors including TIZ-fatty acids ion-pair, drug loading and permeation enhancer were investigated by ex-vivo transdermal experiments. Optimized patch was evaluated by pharmacokinetics study. The better polarity similarity and strong hydrogen bonding interactions between TIZ-caproic acid ion-pair (TIZ-C6) and PSA was confirmed by polarity determination, FT-IR, TOPEM of MDSC and theoretical calculation, which determined enhanced miscibility of ion-pair and PSA. The permeation enhancer affected status of ion-pair in PSA by regulating polarity similarity and interaction between ion-pair and PSA, resulting in increased drug-PSA miscibility and drug release, which was characterized by FT-IR, polarity determination, thermal analysis and molecular dynamics simulation. The optimized patch showed high drug-polymer miscibility and drug skin permeability with AUC0-t of 14641.12 ± 854.45 h ng/mL and Cmax of 834.55 ± 155.68 ng/mL, which was significantly higher than the control group. In conclusion, DIA patch of TIZ was prepared and it supplied a reference for design of DIA patches with TIZ.

Investigation of Drug–Polymer Miscibility, Molecular Interaction, and Their Effects on the Physical Stabilities and Dissolution Behaviors of Norfloxacin Amorphous Solid Dispersions

This study investigated the drug–polymer miscibility, intermolecular interaction, physical stability, and dissolution performance of amorphous solid dispersions (ASDs) of norfloxacin (NFX) with pol...

Thermodynamic, Spatial and Methodological Considerations for the Manufacturing of Therapeutic Polymer Nanoparticles

PurposeEvaluate fundamental parameters that dictate the effectiveness of drug loading.MethodsA model water-soluble drug lacking ionizable groups, pirfenidone (PFD), was encapsulated through nanoprecipitation in poly(ethylene glycol)-poly(lactic acid) (PEG-PLA)-poly(lactic-co-glycolic acid) (PLGA) NPs. Firstly, the thermodynamic parameters predicting drug-polymer miscibility were determined to assess the system’s suitability. Then, the encapsulation was evaluated experimentally by two different techniques, bulk and microfluidic (MF) nanoprecipitation. Additionally, the number of molecules that fit in a particle core were calculated and the loading determined experimentally for different core sizes. Lastly, the effect of co-encapsulation of α-lipoic acid (LA), a drug with complementary therapeutic effects and enhanced lipophilicity, was evaluated.ResultsThe thermodynamic miscibility parameters predicted a good suitability of the selected system. MF manufacturing enhanced the encapsulation efficiency by 60–90% and achieved a 2-fold higher NP cellular uptake. Considering spatial constrictions for drug encapsulation and increasing the size of the PLGA core the number of PFD molecules per NP was raised from under 500 to up to 2000. More so, the co-encapsulation of LA increased the number of drug molecules per particle by 96%, with no interference with the release profile.ConclusionsThermodynamic, spatial and methodological parameters should be considered to optimize drug encapsulation.

Development of 3D Printed Tablets by Fused Deposition Modeling Using Polyvinyl Alcohol as Polymeric Matrix for Rapid Drug Release

In this study, the processability of polyvinyl alcohol (PVA), a water-soluble polymer, into melt-extruded filaments and then into 3D printed tablets by fused deposition modeling was studied. PVA is semicrystalline with Tg and m.p. of ~45°C and ~190°C, respectively. After screening several plasticizers, sorbitol was selected to enhance melt extrudability of PVA. Carvedilol and haloperidol, 2 basic compounds with pH-dependent solubility, were used as model drugs. Miscibility of the drugs with PVA, with and without added sorbitol as plasticizer, was also tested to determine whether any amorphous solid dispersion was formed that would facilitate rapid and pH-independent dissolution. Finally, the drug release from physical mixtures, crushed extrudates, and printed tablets were determined. Owing to high m.p. and high melt viscosity of PVA, filaments containing 10% and 20% drug required 180°C-190°C for extrusion, which could be reduced to ~150°C by adding 10% sorbitol. The printing temperature of 210°C was, however, required. Miscibility of carvedilol and haloperidol with PVA were, respectively, ~20% and <10%. PVA provided complete drug release from 3D printed tablets with 10% and 20% carvedilol and 60% infill in ~45 min at both pH 2 and 6.8. However, despite relatively rapid dissolution rate, high processing temperature and limited drug-polymer miscibility could be potential development issues with PVA.

The Improved Cargo Loading and Physical Stability of Ibuprofen Orodispersible Film: Molecular Mechanism of Ion-Pair Complexes on Drug-Polymer Miscibility

High drug cargo loading in polymer and physical stability was essential for the development of orodispersible films (ODFs) because of the small amount of excipients used in a thin film. The present study aimed to investigate the mechanism of ion-pair strategy in improving drug cargo loading and physical stability of drug in ODFs. The results showed that the ion pair, especially ibuprofen-ethanolamine, improved the drug solubility in polymer up to 60% (w/w) and physical stability by 30% than the pure ibuprofen film. In addition, drug dissolution rate was increased over 2 times. The high drug cargo loading, physical stability and drug dissolution rate was derived from the improved the drug-polymer miscibility introduced by the formation of ion-pair complex. Investigations from the standpoint of physicochemical properties, intermolecular interaction, and polymer mobility indicated the modulation mechanism of ion-pair complexes in the ODFs at molecular level. The amino group and −OH of counter ion exhibited strong hydrogen bond forming ability, which increased the bilateral interaction with both drug and polymer, delayed the onset temperature of sublimation and decreased the polymer mobility. Therefore, ion-pair technology is a promising strategy for high drug loading ODFs in improving the drug-excipient miscibility and stability.

Investigation on the effect of deep eutectic formation on drug-polymer miscibility and skin permeability of rotigotine drug-in-adhesive patch.

The aim of present study was to develop a rotigotine (ROT) transdermal patch by converting ROT to a form of deep eutectic 'liquid co-crystal'. Formulation factors including the type of ROT-organic acid deep eutectics, pressure sensitive adhesives (PSAs), drug-loading and patch thickness were investigated by in vitro skin permeation study and the optimized patch was evaluated by pharmacokinetics study. It was particularly concerned about the drug-polymer miscibility and skin permeability of ROT-lactic acid deep eutectics (ROT-LA). FTIR study, thermal analysis and molecular modeling were conducted to investigate the drug-PSA interaction. Multiple linear regression was performed to investigate the mechanism of the promoted skin permeability. The results showed that strong interaction was observed between ROT-LA and hydroxyl PSA, which inhibited the formation of ROT crystals. Skin permeability of ROT-organic acids deep eutectics were improved by the variations of apparent partition coefficient and glass transition temperature. AUC0-t and Cmax of optimized patch were 1290.6±102.7hng/mL and 60.7±12.0ng/mL, respectively, which had no significant difference with commercial product. In conclusion, a reduced administration area (75%) and low risk of crystallization were introduced by the ROT deep eutectics, which demonstrated the feasibility of improving drug-polymer miscibility and skin permeability of transdermal drug.

Investigation of drug-polymer miscibility, biorelevant dissolution, and bioavailability improvement of Dolutegravir-polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer solid dispersions

The aim of the current study was to prepare the efficacious amorphous solid dispersion of poorly water-soluble compound, Dolutegravir. After theoretical and experimental determination of drug-polymer miscibility, polyvinyl caprolactam-polyvinyl acetate-polyethylne glycol graft copolymer was chosen as a polymer. The solid dispersions of Dolutegravir were prepared by quench cooling and solvent evaporation method. Though quench cooling successfully stabilized the drug into amorphous form, solvent evaporation technique failed to render the drug completely amorphous. Owing to the negative Gibbs free energy at room temperature, the prepared dispersions were found stable at room temperature for 60 days. To resolve the overlapping contribution of micellar solubilization and amorphicity in improving the dissolution characteristics of Dolutegravir, the in vitro dissolution studies were performed in USP phosphate buffer as well as bio-relevant media. The dissolution advantage between prepared dispersions and pure drug in USP phosphate buffer was found bridged in the bio-relevant media. For this, the micellar solubilization driven dissolution of Dolutegravir in the presence of bile and lecithin micelles was thought as a contributing factor. Nevertheless, the dissolution advantage of dispersions prepared by quench cooling method was found endured in FeSSIF, which was thought to be due to its amorphicity leading to molecular level dissolution. Subsequently, the dissolution advantage was translated into the improved flux. Further, in vivo oral bioavailability was investigated for the dispersion prepared by quench cooling by using crystalline Dolutegravir as a control. The overall exposure of Dolutegravir was improved by 1.7 fold (AUC), while the maximum plasma concentration (Cmax) demonstrated 2 fold increase after comparing with crystalline Dolutegravir.