Solid Dispersion Carrier Research Articles

In Vitro Studies on Binary Mixture of Skimmed Milk and Urea as Solid Dispersion Carrier for Aceclofenac

Among the various strategies employed to enhance solubility, dissolution and bioavailability of poorly soluble drugs in vivo, formulation of solid dispersion using hydrophilic and/or water-soluble carriers with varying physicochemical characteristics seems to be a developable, economically viable and easy option. The present study is aimed to use skimmed milk(SKM)-urea(U) as a novel binary mixture of classical carrier-hydrotrope in solid dispersion of poorly water-soluble aceclofenac (ACF). Compatibility of ACF and binary mixture of SKM-U was confirmed by FTIR spectroscopic analysis. Solid dispersions of ACF-SKM and ACF-SKM-U were prepared in varying ratios of 1:1 to 1: 5 for ACF-SKM and 1:4.5:0.5, 1:4.25:0.75 and 1:4:1 for ACF-SKM-U by solvent evaporation technique using ethanol(95%) as the common solvent and were characterised by their physical appearance, solubility enhancement (compared to pure drug) in double distilled water and phosphate buffer (pH 6.8) at 25 ⁰C and drug dissolution profiles in the above mentioned media. Based on solubility enhancement data(71.53% and 31.03%) and maximum cumulative percentage release data (82.37% in 9 mins and 68.03% in 90 secs ) in double distilled water and phosphate buffer respectively, ACF-SKM (1:5) was found to the best which was used for studying the effect of addition of urea as hydrotrope. ACF: SKM: U (1 : 4.5 : 0.75) exhibited maximum solubility enhancement of 75% .and 36.51% and cumulative percentage release of 83.83 % in 9 mins and 69.24% in 90 secs in double distilled water and buffer respectively. Therefore, the binary mixture of skimmed milk-urea has been proved to be marginally superior over skimmed milk in terms of solubility enhancement and drug release profile of aceclofenac.

Improvement of Oral Absorption of Poorly Water-Soluble Drugs by Solid Dispersions with Amphiphilic Phospholipid Polymer

Solid dispersions are one of methods for solubilizing water-insoluble drugs. To enhance the bioavailability, maintenance of the supersaturated state and absorption of the dissolved drug in the gastrointestinal tract are important. We designed and synthesized amphiphilic 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymers as carriers for solid dispersions and evaluated the dissolution behavior in test solutions with different pH and additives. Solid dispersion of troglitazone with amphiphilic MPC copolymers having both aromatic rings and urethane bonds in the side chains showed rapid dissolution and excellent supersaturation maintenance. It was indicated that the balance between the interactions with drug molecules and the water affinity of the polymer should be considered when carriers for solid dispersions are designed. In addition, cell membrane permeability of the solid dispersion with the amphiphilic MPC copolymer was evaluated by the Dissolution / Permeation system, which consists of two liquid chambers and a monolayer of epithelial cells that mimics the intestinal dissolution and permeation process. Further, blood concentration of the drug when solid dispersions were orally administered in mice was also evaluated. The cell membrane permeability and oral absorbability were significantly improved, compared to the solid dispersions with poly(N-vinylpyrrolidone) and suspension or solution of crystalline troglitazone.

Application of mesoporous calcium silicate nanoparticles as a potential SD carrier to improve the solubility of curcumin

Curcumin is a natural polyphenol exhibiting potentials in anti-inflammatory, antioxidant, anti-tumor, and tissue regeneration. Despite its biological significances, the extremely low solubility of curcumin is a serious impediment to its clinical practice. In this study, a curcumin-calcium silicate solid dispersion was prepared via a classical ethanol-based solvent evaporation, in which mesoporous calcium silicate (mesoCS) was applied as dispersion medium aimed to improve water solubility and bioavailability of curcumin. The physicochemical properties of the resulting solid dispersions were characterized by FTIR, XRD, SEM, TEM, DSC, and BET, respectively. In addition, loaded curcumin revealed a curcumin/mesoCS weight ratio depended dissolution improvement and over 60% of curcumin dissolved in the first 5 min for 1/9 weight ratio group. The released curcumin showed a 3410-fold increase of solubility of the original one, accompanied with anti-oxidant activity preservation. These results suggest mesoCS can be a potential solid dispersion carrier for curcumin in oral administration.

Solubility enhancement of some poorly soluble drugs by solid dispersion using Ziziphus spina-christi gum polymer

A high percentage of marketed drugs suffer from poor water solubility and require an appropriate technique to increase their solubility. This study aims to compare physically modified and unmodified gum polymers extracted from Ziziphus spina-christi fruits as solid dispersion carriers for some drugs. Taguchi Orthogonal Design (L9) was chosen for the screening and optimization of the solid dispersions. The design has four factors: type of drug, type of polymer, type of solid dispersion process, and drug to polymer ratio. Each factor was varied in three stages and the total number of runs was 9 in triplicate. The polymer was physically modified by heating (M1ZG) or freeze-drying (M2ZG). The drugs were selected according to the biopharmaceutical classification system, namely loratadine and glimepiride (class II) and furosemide (class IV). Drugs were dispersed in the polymer in three different ratios 1: 1, 1: 2, and 1: 3. Solid dispersions were made by co-grinding, solvent evaporation, and kneading methods. Modified and unmodified polymers were characterized in terms of their organoleptic properties, solubility, powder flowability, density, viscosity, swelling index, and water retention capacity. Solid dispersions were characterized in terms of percentage practical yield, solubility improvement, and drug compatibility. The results showed that the organoleptic properties of polymers were not changed by the gum modification. The swelling index of the polymer was doubled in M1ZG. The viscosity and water retention capacity of the polymer was increased in both modified polymers. All solid dispersions showed a high practical percentage yield of more than 93%, the higher values ​​being more associated with loratadine and furosemide than with glimepiride. The improvement in solubility was observed in all solid dispersions prepared, the values ​​varying with the pH of the medium and the method of modification. The FTIR results indicated that there was no chemical interaction between these drugs and the polymer used. Analysis of the results according to the Taguchi orthogonal design indicated 51 folds aqueous solubility enhancement for loratadine using M2ZG polymer at a ratio of 1: 3 of Drug: polymer. This study showed the possibility of improving the solubility of other poorly soluble drugs.

Development of starch/chitosan expandable films as a gastroretentive carrier for ginger extract-loaded solid dispersion

Gastroretentive expandable films were developed to provide controlled release of ginger extract (GE) for treatment of gastric diseases. The dosage form consisted of ginger extract solid dispersion (GE-SD) loaded in a starch/chitosan composite film, which was subsequently folded and inserted into a hard gelatin capsule. GE-SD was prepared by solvent evaporation using an optimum weight ratio of 1:1 for GE and PVP K30. Expandable films containing GE-SD were prepared by solvent casting combinations of chitosan and either rice-, glutinous rice - or pregelatinized maize starch with glycerin incorporated as a plasticizer. The optimized film formulation prepared from glutinous rice starch, exhibited tensile strength of 5.4 N/cm2 and high expansion in simulated gastric fluid (SGF), resulting in a 2.8-fold increase in area. The films resulted in sustained release of up to 90% of the content of 6-gingerol during 8 h exposure to SGF. Furthermore, the 6-gingerol released from the film displayed dose-dependent cytotoxic activity against AGS human gastric adenocarcinoma cells and anti-inflammatory activity by inhibiting the production of nitric oxide (NO) in LPS-stimulatedRAW264.7cells.

Tablet formulation development focusing on the functional behaviour of water uptake and swelling

The functional behaviour of tablets is strongly influenced by their manufacturing process and the choice of excipients. Water uptake and swelling are prerequisites for tablet disintegration, dispersion and hence active pharmaceutical ingredient (API) dissolution. High proportions of polymeric excipients in tablets, which are typically used as API carriers in amorphous solid dispersions (ASDs), may be challenging due to the formation of a gelling polymer network (GPN). In this study, systematic investigations into the formulation development of tablets containing polymeric and other excipients are performed by water uptake and swelling analysis. The impact of tablet composition and porosity as well as pH of the test medium are investigated. The pH affects the analysis results for Eudragit L100–55 and Eudragit EPO. HPMC and Kollidon VA64 inhibit water uptake and swelling of tablets due to the formation of a GPN. High tablet porosity, coarse particle size of the polymer and the addition of fillers and disintegrants can reduce the negative impact of a GPN on tablet performance. The application of lubricants slows down the analysed processes. Water uptake and swelling data are fitted to an empirical model obtaining four characteristic parameters to facilitate the simple quantitative assessment of varying tablet formulations and structural properties.

Recovery of glucosamine and optimization of chitin extraction with acid and alkali process from shells of sea mussel Mytilus galloprovincialis in Greece

Mussel wastes include byproducts such as seed, barnacles fouling, broken shells, byssus threads, which are associated with serious environmental impacts on aquatic ecosystems. The objective of reducing wastes and to avoid environmental problems can be achieved by establishing alternative methods to valorize mussel wastes converting them into high value-added products. The present study aims to obtain by chemical methods the extraction of chitin and glucosamine from shells of Mytilus galloprovincialis. Chitin, which chemically is a linear polysaccharide of β (1→4) linked N-acetylglucosamine monomers, possesses multifunctional properties and is suitable for various applications mainly in pharmaceutical, biomedical food and packaging fields. Glucosamine (C6H13NO5) is an amino sugar (2-amino-2-deoxy-β-D-glucopyranose) and is a part of the structure of two polysaccharides, chitosan and chitin. Due to its high aqueous solubility and physical stability is used as a potential solid-dispersion carrier to improve the biopharmaceutical properties of drugs. The influence of temperature, solid/liquid ratio (g/ml), molarity of solutions and agitation on chitin production and acid hydrolysis of chitin was studied to achieve optimum output of chitin and glucosamine. Our results demonstrates that the production of glucosamine and chitin is greatly influenced by the experimental conditions. The best yield for glucosamine was obtained at a solid/liquid ratio of 1:15 at 60°C for 1 hour.

New potential application of hydroxypropyl-β-cyclodextrin in solid self-nanoemulsifying drug delivery system and solid dispersion

The purpose of this study was to use hydroxypropyl-β-cyclodextrin (HP-β-CD) as a novel carrier in solid SNEDDS and solid dispersions to enhance the solubility and oral bioavailability of poorly water-soluble dexibuprofen. The novel dexibuprofen-loaded solid SNEDDS was composed of dexibuprofen, corn oil, polysorbate 80, Cremophor® EL, and HP-β-CD at a weight ratio of 45/35/50/15/100. This solid SNEDDS spontaneously formed a nano-emulsion with a size of approximately 120 nm. Unlike the conventional solid SNEDDS prepared with colloidal silica as a carrier, this dexibuprofen-loaded solid SNEDDS exhibited a spherical structure. Similar to the dexibuprofen-loaded solid dispersion prepared with HP-β-CD, the transformation of the crystalline drug to an amorphous state with no molecular interactions were observed in the solid SNEDDS. Compared to the solid dispersion and dexibuprofen powder, solid SNEDDS significantly enhanced drug solubility and AUC. Therefore, HP-β-CD is a novel potential carrier in SNEDDS for improving the oral bioavailability of dexibuprofen.

Applicability of an Experimental Grade of Hydroxypropyl Methylcellulose Acetate Succinate as a Carrier for Formation of Solid Dispersion with Indomethacin.

The transformation of a crystalline drug into an amorphous form is a promising way to enhance the oral bioavailability of poorly water-soluble drugs. Blending of a carrier, such as a hydrophilic polymer, with an amorphous drug is a widely used method to produce a solid dispersion and inhibit crystallization. This study investigates an experimental grade of hydroxypropyl methylcellulose acetate succinate, HPMCAS-MX (MX), as a solid dispersion carrier. Enhancement of thermal stability and reduction of the glass transition temperature (Tg) of MX compared with those of the conventional grade were evaluated through thermogravimetric analysis and differential scanning calorimetry (DSC). The formation of a homogeneous amorphous solid dispersion between MX and indomethacin was confirmed by X-ray powder diffraction analysis, DSC, and Raman mapping. It was observed that 10–30% MX did not act as an anti-plasticizer, but the utilization of >40% MX caused an increase in Tg and reduction of molecular mobility. This could be explained by a change in intermolecular interactions, inferred from infrared spectroscopy combined with principal component analysis. HPMCAS-MX exhibited similar performance to that of conventional-grade, HPMCAS-MG. Although HPMCAS-MX has thermal properties different from those of conventional-grade HPMCAS-MG, it retains its ability as a solid dispersion carrier.

Egg White Protein Carrier-Assisted Development of Solid Dispersion for Improved Aqueous Solubility and Permeability of Poorly Water Soluble Hydrochlorothiazide.

Hydrochlorothiazide (HTZ) is a first-line drug used in the treatment of hypertension suffered from low oral bioavailability due to poor aqueous solubility and permeability. Hence, lyophilized egg white protein-based solid dispersion (HTZ-EWP SD) was developed to explore its feasibility as a solid dispersion carrier for enhanced aqueous solubility and permeability of HTZ. The HTZ-EWP SD was prepared using the kneading method. HTZ-EWP SD was characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transforms infrared spectroscopy (FT-IR), powder X-ray diffractometer (PXRD), solubility, in vitro dissolution, and ex vivo permeation studies. The physico-chemical evaluation suggested the formation of the solid dispersion. Optimized HTZ-EWP SD4 drastically enhanced (~32-fold) aqueous solubility (~16.12 ± 0.08 mg/mL) over to pure HTZ (~ 0.51 ± 0.03 mg/mL). The dissolution study in phosphate buffer media (pH 6.8) revealed that HTZ-EWP SD4 significantly enhanced the release rate of HTZ (~ 87 %) over to HTZ (~ 25 %). The permeation rate of HTZ from optimized HTZ-EWP SD4 was enhanced significantly (~ 84 %) compared to pure HTZ (~ 24 %). Optimized HTZ-EWP-SD4 enhanced the rate of HTZ dissolution (~ 86 %) in FeSSIF (fed state simulated intestinal fluid), compared to a low dissolution rate (~ 72 %) in FaSSIF (fasted state simulated intestinal fluid) state after 2-h study. Obtained results conclude that lyophilized egg white protein can be utilized as an alternative solid dispersion carrier for enhancing the solubility and permeability of HTZ.

Development of Controlled-Release Carbamide Peroxide Loaded Nanoemulgel for Tooth Bleaching: In Vitro and Ex Vivo Studies.

Burst release of carbamide peroxide (CP) from traditional hydrogels causes severe inflammation to periodontal tissues. The present study explores the development of a novel CP nanoemulgel (CP-NG), an oil-in-water nanoemulsion-based gel in which CP was loaded with a view to controlling CP release. CP solid dispersions were prepared, using white soft paraffin or polyvinylpyrrolidone-white soft paraffin mixture as a carrier, prior to formulating nanoemulsions. It was found that carrier type and the ratio of CP to carrier affected drug crystallinity. Nanoemulsions formulated from the optimized CP solid dispersions were used to prepare CP-NG. It was found that the ratio of drug to carrier in CP solid dispersions affected the particle size and zeta potential of the nanoemulsions as well as drug release behavior and tooth bleaching efficacy of CP-NG. Drug release from CP-NG followed a first-order kinetic reaction and the release mechanism was an anomalous transport. Drug release rate decreased with an increase in solid dispersion carriers. CP-NG obtained from the solid dispersion with a 1:1 ratio of CP to the polymer mixture is suitable for sustaining drug release with high tooth bleaching efficacy and without reduction of enamel microhardness. The developed CP-NG is a promising potential tooth bleaching formulation.

Phase behavior of ASDs based on hydroxypropyl cellulose

Novel polymeric carriers for amorphous solid dispersions (ASDs) are highly demanded in pharmaceutical industry to improve the bioavailability of poorly-soluble drug candidates. Besides established polymer candidates, hydroxypropyl celluloses (HPC) comes more and more into the focus of ASD production since they have the availability to stabilize drug molecules in aqueous media against crystallization. The thermodynamic long-term stability of HPC ASDs with itraconazole and fenofibrate was predicted in this work with PC-SAFT and compared to three-months enduring long-term stability studies. The glass-transition temperature is a crucial attribute of a polymer, but in case of HPC hardly detectable by differential scanning calorimetry. By investigating the glass transition of HPC blends with a miscible polymer, we were for the first time able to estimate the HPC glass transition. Although both, fenofibrate and itraconazole reveal a very low crystalline solubility in HPC regardless of the HPC molecular weight, we observed that low-molecular weight HPC grades such as HPC-UL prevent fenofibrate crystallization for a longer period than the higher molecular weight HPC grades. As predicted, the ASDs with higher drug load underwent amorphous phase separation according to the differential scanning calorimetry thermograms. This work thus showed that it is possible to predict critical drug loads above which amorphous phase separation and/or crystallization occurs in HPC ASDs.

Enhancement of the solubility and the dissolution rate of oral nimodipine formulation with solid dispersion

The present study was an attempt to enhance the dissolution rate of nimodipine (a poorly water-soluble drug), The objective of this study was to evaluate poloxamer 407 as a carrier for nimodipine solid dispersions. The solid dispersions of nimodipine with poloxamer 407 were prepared by the hot melting technique, the molar ratio (3:1). The physicochemical properties of Solid dispersion were investigated by Differential Scanning Calorimetry (DSC), powder x-ray diffraction (PXRD), and Fourier Transform Infrared (FT-IR) spectroscopy. The FT-IR spectra indicated there was no chemical interaction between nimodipine and poloxamer 407 in the solid dispersion. DSC analysis indicated a decrease in the melting point of nimodipine and poloxamer 407 in solid dispersion. The tablet form was prepared by wet granulation of nimodipine with a binder solution of poloxamer 407 and compressed the dried granules of nimodipine into non-friable, stable tablets. The other objective, the performance of two classes of super disintegrates as croscarmellose sodium (Ac-Di-Sol), and polyvinyl pyrrolidone K30 in the dissolution of nimodipine immediate release and promoting disintegration tablets was evaluated. The in-vitro dissolution was determined by using United States Pharmacopeia (USP) type II dissolution test apparatus. All the results indicated that enhancement of the dissolution rate of nimodipine has been done successfully and drug release Kinetics indicated that the drug dissolution was a diffusion equation.

Hyperbranched poly(glycerol esteramide): A biocompatible drug carrier from glycerol feedstock and dicarboxylic acid

AbstractPolymer carrier with biodegradable, biocompatible as well as solubility enhancing properties are highly looked upon in the pharmaceutical industry to improve the drug delivery systems. A series of hyperbranched poly(glycerol esteramide) (HPGEA) with Mw of 5000–12,000 Da, degree of branching of 57%–62%, and hydroxyl values of 200–280 mg KOH/g sample were synthesized through polycondensation of N,N‐bis(2‐hydroxyethyl)stearamide (diethanolamide) and poly(glycerol ester) (PGE). The HPGEAs were characterized by ATR‐FTIR, GPC, 1H and 13C‐NMR, and DSC. The enthalpy of fusion of HPGEAs (43–84 J g−1) were lower than the commercial polymers (193–391 J g−1), indicating its potential as drug carrier for solid dispersion (SD). HPGEA‐based SDs showed substantial enhancement in solubility and release rate than pure drug, commercial polymer‐based SDs, as well as commercial formulation. The safety of HPGEAs and HPGEA‐based SDs were proven through MTT assay with IC50 of 2400–9800 and 1200–3500 μg ml−1, respectively.

Determining the Best Poloxamer Carrier for Thiocolchicoside Solid Dispersions.

The aim of this study of this study was to discover the best poloxamer as a solid dispersion carrier for thiocolchicoside (TCS). The compatibility of TCS with excipients was studied by differential scanning colorimetry and fourier transform infrared spectroscopy. Different formulations of solid dispersions (SDs) were made with poloxamer carriers, i.e. poloxamer-108, poloxamer-188, poloxamer-237, poloxamer-338, and poloxamer-407 were made by taking TCS:poloxamer in ratios of 1:1, 1:2, 1:4, and 1:6. The SDs were made by a novel microwave fusion method and compressed using an 8-station tablet compression machine. The fabricated SD tablets were characterized by physicochemical constraints and drug release rates. The release of TCS from the prepared SDs was later analyzed by kinetic models. TCS was observed to be compatible with the poloxamer carriers. The SD formulations showed satisfactory physicochemical constraints and TCS release following first-order release. Among the poloxamer carriers used, poloxamer-188 was the best for increasing the solubility and release rate of TCS from the SDs.

Evolution of supersaturation from amorphous solid dispersions in water-insoluble polymer carriers: Effects of swelling capacity and interplay between partition and diffusion.

The use of water-insoluble carriers for amorphous solid dispersions (ASDs) has attracted more recent interest as the kinetic solubility profiles (KSP) from these systems can achieve a more sustained level of supersaturation when compared with ASDs based on water-soluble polymers. However, the effect of swelling capacity of water-insoluble carriers on the resulting KSP of ASDs has not been fully explored in terms of their achievable degree and extent of drug supersaturation. Thus, the objective of this study is to compare kinetic solubility profiles of ASDs based on commercially available water-insoluble carriers in order to bridge this knowledge gap and provide fundamental information important to the design of ASDs based on water-insoluble carriers. This was achieved by comparing the KSP from non-sink dissolution studies of ASDs of two model poorly-water soluble drugs, indomethacin (IND) and posaconazole (PCZ) based on commercially available water-insoluble carriers with different equilibrium water swelling such as fully hydrolyzed (physically crosslinked) poly (vinyl alcohol) (PVA), Eudragit RS PO, as well as chemically crosslinked PHEMA hydrogels . Our results show that the higher the swelling capacity of the water-insoluble carrier, the faster the rate of supersaturation generation, and the shorter the sustained supersaturation due to drug precipitation. The interplay of particle size, total dose and the swelling capacity was also shown to be an essential aspect when tailoring the supersaturation generation from water-insoluble polymer-based ASDs. The importance of the swelling feature was confirmed using firstly different polymer carriers (PVA, Eudragit RS PO, and PHEMA) and then polymer samples of identical composition and drug loading but with different swelling capacities (e.g., PVA, physically crosslinked to different degrees). Furthermore, a large drug partitioning value between the polymer carrier and dissolution medium was found to limit the extent of drug release or supersaturation buildup from these ASDs. Finally, the existence of electrostatic polymer-drug interactions realized from our molecular dynamic simulations supports the observed impact of the large partitioning of the model drug IND between the polymer ED RS PO and the dissolution medium, thereby leading to a lower degree of supersaturation generation (or slower drug release) from this ASD.

Solid state nuclear magnetic resonance studies of hydroxypropylmethylcellulose acetyl succinate polymer, a useful carrier in pharmaceutical solid dispersions.

Hydroxypropylmethylcellulose (HPMC) acetyl succinate (HPMC-AS) is a key polymer used for the enablement of amorphous solid dispersions (ASDs) in oral solid dosage forms. Choice of the appropriate grade within the material is often made empirically by the manufacturer of small-scale formulations, followed by extensive real time stability. A key factor in understanding and predicting the performance of an ASD is related to the presence of hydrogen (or other) bonds between the polymer and active pharmaceutical ingredient (API), which will increase stability over the parameters captured by miscibility and predicted by the Gordon-Taylor equation. Solid state nuclear magnetic resonance (NMR) is particularly well equipped to probe spatial proximities, for example, between polymer and API; however, in the case of HPMC-AS, these interactions have been sometimes difficult to identity as the carbon-13 NMR spectra assignment is yet to be firmly established. Using feedstock, selectively substituted HPMC polymers, and NMR editing experiments, we propose here a comprehensive understanding of the chemical structure of HPMC-AS and a definitive spectral assignment of the 13 C NMR spectra of this polymer. The NMR data also capture the molar ratios of the acetate and succinate moieties present in HPMC-AS of various grades without the need for post treatment required by chromatography methods commonly use in pharmacopoeia. This knowledge will allow the prediction and measurement of interactions between polymers and APIs and therefore a rational choice of polymer grade to enhance the solid state stability of ASDs.

FORMULATION AND OPTIMIZATION OF CURCUMIN SOLID DISPERSION PELLETS FOR IMPROVED SOLUBILITY

Objective: The present study was aimed at designing of solid dispersion based pellets of curcumin (Cu) for improving its solubility.
 Methods: Solid dispersion (SD) of Cu was prepared by the melt method using Poloxamer 407 (Pol 407) at a different weight ratio of Cu-Pol 407 (1:2, 1:3, 1:5, 1:7, 1:10). The solid dispersion was characterised by FTIR, SEM, DSC, XRD and evaluated for saturation solubility in water, drug content and in vitro dissolution. The pellets of Cu solid dispersion were prepared by extrusion spheronization technique and optimization was performed by 32full factorial design. The pellets were evaluated for size distribution, flow properties, hardness, disintegration and in vitro drug dissolution.
 Results: From the phase solubility analysis, Pol 407 was selected as a Solid dispersion carrier. The formation of Cu-SD by melt method using Pol 407, was confirmed from FTIR and DSC studies. XRD studies indicated a change of Cu from crystalline to amorphous form. There was a significant increase of Cu when formulated as SD compared to plain Cu. The optimization of extrusion spheronization process revealed the significant effect of Cu-Pol 407 ratio (p<0.0001) on in vitro dissolution of pellets. Higher Cu dissolution was obtained with Cu-SD pellets compared to plain Cu pellets.
 Conclusion: The present study demonstrated the potential of Cu-SD pellets in improving the solubility of poorly soluble Cu.

Understanding the interaction between Soluplus® and biorelevant media components

Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) is a solubilizing copolymer commonly applied as carrier in solid dispersions of poorly soluble drugs. This polymer is used to increase the apparent solubility of drugs with low aqueous solubility and consequently enhance drug absorption by the human gastrointestinal tract. To select the appropriate carrier to compose solid dispersions, in vitro supersaturation studies were applied as a pre-formulation tool, using different dissolution media. During in vitro supersaturation studies performed for the poorly soluble drug candesartan cilexetil, it was found that Soluplus® may interact with components of the biorelevant medium Fasted State Simulated Intestinal Fluid, lowering the drug apparent solubility. Dynamic Light Scattering and Transmission Electron Microscopy analyses were performed, as well as fluorescence measurements, aiming to characterize the interaction behavior and determine the polarity of the microenvironment. It was evidenced that Soluplus® interacted preferentially with lecithin, forming mixed micelles with a more polar microenvironment, which lowered the candesartan cilexetil solubilization capacity and consequently reduced its apparent solubility in the biorelevant medium. These findings are important to emphasize the key role of the media selection for in vitro solubility-supersaturation studies, where media that could mimic the human gastrointestinal environment are recommended.

Effects of Surfactants on Itraconazole-Hydroxypropyl Methylcellulose Acetate Succinate Solid Dispersion Prepared by Hot Melt Extrusion III: Tableting of Extrudates and Drug Release From Tablets

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) has gained popularity as a carrier for amorphous solid dispersion because of its ability to maintain drugs in supersaturated state after dissolution in aqueous media. In part I and II of this series of articles, we have demonstrated that amorphous solid dispersions containing HPMCAS may be prepared using surfactants as plasticizers to reduce processing temperature (Solanki et al., J Pharm Sci. 2019; 108:1453-65), where surfactants also increase dissolution rate and degree of supersaturation (Solanki et al., J Pharm Sci. 2019; 108: 3063-73). The present investigation was undertaken to develop melt extrudates of itraconazole-HPMCAS and itraconazole-surfactant-HPMCAS mixtures into tablets having tensile strength ≥2 MPa, where poloxamer 407 and d-α-tocopherol polyethylene glycol 1000 succinate were used as surfactants. Milled filaments were sieved to collect <212-μm particles, which were then compressed into tablets with different excipients (silicified microcrystalline cellulose [MCC], Avicel PH-102, dicalcium phosphate, lactose, and Starch 1500). Initial screening of various diluents showed that only silicified MCC and Avicel PH-102 could provide the target tensile strength of ≥2 MPa. Tabletability (tensile strength vs. compaction pressure), compressibility (porosity vs. compaction pressure), and compactibility (tensile strength vs. porosity) were then studied for tablet formulations. The desired tensile strength could be obtained at the diluent level of 50%-70%, where silicified MCC provided better hardness than Avicel PH-102. Tablets disintegrated in <2 min, and drug release from tablets was comparable to that of milled filaments.