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

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

Formulation of 3D Printed Tablet for Rapid Drug Release by Fused Deposition Modeling: Screening Polymers for Drug Release,Drug-Polymer Miscibility and Printability

The primary aim of this study was to identify pharmaceutically acceptable amorphous polymers for producing 3D printed tablets of a model drug, haloperidol, for rapid release by fused deposition modeling. Filaments for 3D printing were prepared by hot melt extrusion at 150°C with 10% and 20% w/w of haloperidol using Kollidon^® VA64, Kollicoat^® IR, Affinsiol^?15 cP, and HPMCAS either individually or as binary blends (Kollidon^® VA64 + Affinisol^? 15 cP, 1:1; Kollidon^® VA64 + HPMCAS, 1:1). Dissolution of crushed extrudates was studied at pH 2 and 6.8, and formulations demonstrating rapid dissolution rates were then analyzed for drug-polymer, polymer-polymer and drug-polymer-polymer miscibility by film casting. Polymer-polymer (1:1) and drug-polymer-polymer (1:5:5 and 2:5:5) mixtures were found to be miscible. Tablets with 100% and 60% infill were printed using MakerBot printer at 210°C, and dissolution tests of tablets were conducted at pH 2 and 6.8. Extruded filaments of Kollidon^® VA64-Affinisol^? 15 cP mixtures were flexible and had optimum mechanical strength for 3D printing. Tablets containing 10% drug with 60% and 100% infill showed complete drug release at pH 2 in 45 and 120 min, respectively. Relatively high dissolution rates were also observed at pH 6.8. The 1:1-mixture of Kollidon^® VA64 and Affinisol^?15 cP was thus identified as a suitable polymer system for 3D printing and rapid drug release.     

Novel oral dosage regimen based on self-nanoemulsifying drug delivery systems for codelivery of phytochemicals – Curcumin and thymoquinone

BackgroundCurcumin and Thymoquinone are very well-known phytochemicals for their potent anti-inflammatory and anticancer properties. The major challenges for curcumin is its poor aqueous solubility and erratic oral bioavailability.ObjectiveTo develop a novel liquid self-nanoemulsifying drug delivery system (SNEDDS) containing curcumin and thymoquinone and further converted into a solid dosage form using adsorbents Syloid® and Neusilin® as the solid carrier.MethodsThe characterization of the liquid and solid SNEDDS was performed by particle size & zeta potential analysis, scanning electron microscopy, differential scanning calorimetry, fourier transform infrared spectroscopy and X-ray powder diffraction. The drug loading, and in vitro release studies were carried out to investigate the efficiency of curcumin release from SNEDDS.ResultsThe liquid SNEDDS containing black seed oil showed excellent self-emulsification performance with transparent appearance. The results of characterization studies showed that solidification using 50% (w/w) Syloid® and Neusilin® in the liquid formulation yield free flowing powder with no agglomeration but Neusilin® produced smooth granules than Syloid® and kept the drugs stable in amorphous state. In vitro dissolution studies indicated that liquid SNEDDS formulations of F4 and its solid SNEDDS using Neusilin® provided high dissolution efficiency and reproducibility for curcumin and thymoquinone. However, Neusilin® showed higher rate of dissolution (more than 65%, p < 0.05) compared to Syloid® for curcumin.ConclusionsCurcumin loaded-SNEDDS formulation containing thymoquinone in liquid & solid dosage forms were successfully developed with an increased drug loading and dissolution rate, which could be the potential combined delivery system for various anti-inflammatory and anti-cancer treatments.     

A Comparison of Spray-Drying and Co-Precipitation for the Generation of Amorphous Solid Dispersions (ASDs) of Hydrochlorothiazide and Simvastatin

Co-processing of APIs, the practice of creating multi-component APIs directly in chemical processing facilities used to make drug substance, is gaining increased attention with a view to streamlining manufacturing, improving supply chain robustness and accessing enhanced product attributes in terms of stability and bioavailability. Direct co-precipitation of amorphous solid dispersions (ASDs) at the final step of chemical processing is one such example of co-processing. The purpose of this work was to investigate the application of different advanced solvent-based processing techniques - direct co-precipitation (CP) and the benchmark well-established spray-drying (SD) process - to the production of ASDs comprised of a drug with a high T_g (hydrochlorothiazide, HCTZ) or a low T_g (simvastatin, SIM) molecularly dispersed in a PVP/VA 64 or Soluplus® matrix. ASDs of the same composition were manufactured by the two different methods and were characterised using powder X-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and scanning electron microscopy (SEM). Both methods produced ASDs that were PXRD amorphous, with some differences, depending on the process used, in glass transition temperature and particle size distribution. Irrespective of manufacturing method used, all ASDs remained PXRD amorphous when subjected to high relative humidity conditions (75% RH, 25°C) for four weeks, although changes in the colour and physical characteristics were observed on storage for spray-dried systems with SIM and PVP/VA 64 copolymer. The particle morphology differed for co-precipitated compared to spray dried systems, with powder generated by the former process being comprised of more irregularly shaped particles of larger particle size when compared to the equivalent spray-dried systems which may enable more streamlined drug product processes to be used for CP materials. These differences may have implications in downstream drug product processing. A limitation identified when applying the solvent/anti-solvent co-precipitation method to SIM was the high antisolvent to solvent ratios required to effect the precipitation process. Thus, while similar outcomes may arise for both co-precipitation and spray drying processes in terms of ASD critical quality attributes, practical implications of applying the co-precipitation method and downstream processability of the resulting ASDs should be considered when choosing one solvent-based ASD production process over another.     

Molecular Mechanisms Involved in Supersaturation of Emodin Ternary Solid Dispersions Based on Bonding Agents

The use of solid dispersions (SDs) is an established method for improving the dissolution rate of poorly water-soluble drugs. However, there have been few studies on the molecular mechanisms contributing to SD supersaturation. Emodin ternary SDs (TSDs) were prepared by hot melt extrusion (HME) using Kollidon® VA64 as the polymer carrier and nicotinamide as the bonding agent. Molecular docking and solubility tests were used to assist screening of polymer carriers, and in vitro dissolution and dissociation constant data were used to optimize the formulation. A variety of analytical methods and molecular dynamics simulations were used to investigate the mechanism of SD supersaturation at the molecular level. The results showed that molecular migration, intermolecular interactions, drug crystal transformation and dissociation constant were particularly important factors in SD supersaturation. This study proposes a new strategy to improve solubility of poorly water-soluble drugs and explore the molecular mechanisms of TSD supersaturation, which could provide a basis for the rational selection of excipients for pharmaceutical preparations.     

Physicochemical Characterization of Felodipine-Kollidon VA64 Amorphous Solid Dispersions Prepared by Hot-Melt Extrusion

To improve the dissolution and hence the oral bioavailability, amorphous felodipine (FEL) solid dispersions (SDs) with Kollidon® VA 64 (PVP/VA) were prepared. Hot-melt extrusion was employed with an extruding temperature below the melting point (T_m) of FEL. X-ray powder diffraction (XRPD) and ¹³C CP/MAS nuclear magnetic resonance (NMR) measurements show that the extrudates are amorphous. The intermolecular interaction between FEL and PVP/VA in SDs was investigated by Fourier transform infrared spectroscopy, ¹⁵N CP/MAS NMR, and ¹H high-resolution MAS NMR. Furthermore, a single glass transition temperature (T_g) was detected by differential scanning calorimetry in addition to a single ¹H T₁ or T_1rho relaxation time detected by ¹³C NMR signals. These results confirm that the extru-dates contain FEL dispersed into the polymer matrix at a molecular level with no detectable phase separation. This molecular-scale mixing results in a significantly faster dissolution rate compared with the pure crystalline FEL. Additionally, the molecular-scale mixing prevents the amorphous drug from recrystallizing even after being stored at 40°C/75% Relative Humidity for 2 months.     

Taste masking of paracetamol by hot-melt extrusion: An in vitro and in vivo evaluation

The purpose of this study was the in vitro and in vivo evaluation of the masking efficiency of hot melt extruded paracetamol (PMOL) formulations. Extruded granules containing high PMOL loadings in Eudragit EPO® (EPO) or Kollidon® VA64 (VA64) were prepared by hot-melt extrusion (HME). The taste masking effect of the processed formulation was evaluated in vivo by a panel of six healthy human volunteers. In addition, in vitro evaluation was carried out by an Astree e-tongue equipped with seven sensors. Taste sensing technology demonstrated taste improvement for both polymers by correlating the data obtained for the placebo polymers and the pure APIs alone. The best masking effect was observed for VA64 at 30% PMOL loading. The e-tongue results were in good agreement with the in vivo evaluation. In vitro dissolution of the extruded granules showed rapid PMOL releases.     

Enhanced kinetic solubility profiles of indomethacin amorphous solid dispersions in poly(2-hydroxyethyl methacrylate) hydrogels

The feasibility of forming solid molecular dispersions of poorly water-soluble drugs in crosslinked poly(2-hydroethyl methacrylate) (PHEMA) hydrogel has recently been reported by our group. The purpose of the present study is to investigate the extent of enhancement of kinetic solubility of amorphous solid dispersions (ASDs) of indomethacin (IND) in crosslinked PHEMA hydrogels as compared with those based on conventional water-soluble polymer carriers. Our results show that under non-sink conditions, the initial solubility enhancement is higher for ASDs based on polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose acetate succinate (HMPCAS), but the ability to maintain this solubility enhancement at longer times is better for ASDs based on PHEMA over a period of 24h with the extent of solubility enhancement of IND ASDs in PHEMA falling between those in PVP and HPMCAS at 10.0% IND loading after 6h and outperforming those in PVP and HPMCAS at 32.9% IND loading after 8h. The observed kinetic solubility profiles reflect the fact that the amorphous IND is released from PHEMA by a different mechanism than those from water-soluble polymer carriers. In this case, the dissolution of IND ASD from water-soluble PVP and HPMCAS is almost instantaneous, resulting in an initial surge of IND concentration followed by a sharp decline due to the nucleation and crystallization events triggered by the rapid build-up of drug supersaturation. On the other hand, the dissolution of IND ASD from insoluble crosslinked PHEMA hydrogel beads is less rapid as it is regulated by a feedback-controlled diffusion mechanism, thus avoiding a sudden surge of supersaturation in the dissolution medium. The absence of an apparent decline in drug concentration during dissolution from IND-PHEMA ASD further reflects the diminished nucleation and crystallization events during IND dissolution from hydrogel-based solid molecular dispersions. Based on the XRD analyses, a threshold IND loading level of about 34% in PHEMA has been identified, above which amorphous to crystalline transition tends to occur. Also, by selecting the appropriate particle sizes, immediate to controlled release of IND from IND-PHEMA ASD can be readily achieved as the release rate increases with decreasing PHEMA bead size. Furthermore, a robust physical stability has been demonstrated in IND-PHEMA ASD with no drug precipitation for up to 8 months at IND loadings below 16.7% under direct open cup exposure to accelerated stability conditions (40°C/75% RH).     

Antisolvent Recrystallization Strategy to Screen Appropriate Carriers to Stabilize Filgotinib Amorphous Solid Dispersions

Drugs in amorphous solid dispersions (ASDs) are highly dispersed in hydrophilic polymeric carriers, which also help to restrain recrystallization and stabilize the ASDs. In this study, microscopic observation after antisolvent recrystallization was developed as a rapid screening method to select appropriate polymers for the initial design filgotinib (FTN) ASDs. Using solvent evaporation, FTN ASDs with the polymers were prepared, and accelerated experimentation validated this screening method. Fourier-transform infrared spectroscopy, Raman scattering, and nuclear magnetic resonance revealed hydrogen-bonding formation in the drug-polymer binary system, which was critical for ASDs stabilization. A Flory-Huggins interaction parameter and water sorption isotherms were applied to evaluate the strength of the interaction between FTN and the polymers. The dissolution rate was also significantly improved by ASDs formulation, and the presence of the polymers exerted solubilization effects. These results suggested the efficacy of this screening method as a preliminary tool for polymer selection in ASDs design.     

Hot Melt Extrudates Formulated Using Design Space: One Simple Process for Both Palatability and Dissolution Rate Improvement

This work aimed at obtaining an optimized itraconazole (ITZ) solid oral formulation in terms of palatability and dissolution rate by combining different polymers using hot melt extrusion (HME), according to a simplex centroid mixture design. For this, the polymers Plasdone^® (poly(1-vinylpyrrolidone-co-vinyl acetate) [PVP/VA]), Klucel^® ELF (2-hydroxypropyl ether cellulose [HPC]), and Soluplus^® (SOL, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol) were processed using a laboratory HME equipment operating without recirculation at constant temperature. Samples were characterized by physicochemical assays, as well as dissolution rate and palatability using an e-tongue. All materials became homogeneous and dense after HME processing. Thermal and structural analyses demonstrated drug amorphization, whereas IR spectroscopy evidenced drug stability and drug-excipient interactions in HME systems. Extrudates presented a significant increase in dissolution rate compared to ITZ raw material, mainly with formulations containing PVP/VA and HPC. A pronounced improvement in taste masking was also identified for HME systems, especially in those containing higher amounts of SOL and HPC. Data showed polymers act synergistically favoring formulation functional properties. Predicted best formulation should contain ITZ 25.0%, SOL 33.2%, HPC 28.9%, and PVP/VA 12.9% (w/w). Optimized response considering dissolution rate and palatability reinforces the benefit of polymer combinations.     

Diclofenac sodium loaded-cellulose acetate butyrate: Effect of processing variables on microparticles properties,drug release kinetics and ulcerogenic activity

The aim of this study was to develop and characterize diclofenac sodium loaded-cellulose acetate butyrate microparticles in order to obtain a controlled-release system. The influence of the type of polymer, the volume and composition of the internal phase, drug loading, surfactant concentration and additive added on microparticles characteristics (particle size, encapsulation efficiency, surface morphology and in vitro release profiles) was studied to optimize the microparticles system. The resultant microparticles were evaluated for the recovery, average particle size, drug loading and incorporation efficiency. The microparticles exhibited good flowing nature and compressibility index when compared to pure drug. Dissolution rate of diclofenac sodium in phosphate buffer (pH 6.8) increased with increases in initial drug loading, surfactant concentration and addition of alcohol as co-solvent but decreased with increases in the concentration of additives such as Gantrez® AN or Eudragit S100 in the internal phase. The dissolution data showed a Higuchi diffusion pattern for most of the formulations. About 56–81% reduction in ulcerogenic activity was observed with microparticles containing Eudragit S100 17–25%, based on total polymer concentration, when compared with pure diclofenac sodium.     

Release Mechanisms of Amorphous Solid Dispersions: Role of Drug-Polymer Phase Separation and Morphology

Formulating poorly soluble molecules as amorphous solid dispersions (ASDs) is an effective strategy to improve drug release. However, drug release rate and extent tend to rapidly diminish with increasing drug loading (DL). The poor release at high DLs has been postulated to be linked to the process of amorphous-amorphous phase separation (AAPS), although the exact connection between phase separation and release properties remains somewhat unclear. Herein, release profiles of ASDs formulated with ritonavir (RTV) and polyvinylpyrrolidone/vinyl acetate (PVPVA) at different DLs were determined using surface normalized dissolution. Surface morphologies of partially dissolved ASD compacts were evaluated with confocal fluorescence microscopy, using Nile red and Alexa Fluor 488 as fluorescence markers to track the hydrophobic and hydrophilic phases respectively. ASD phase behavior during hydration and release of components were also visualized in real time using a newly developed in situ confocal fluorescence microscopy method. RTV-PVPVA ASDs showed complete and rapid drug release below 30% DL, partial drug release at 30% DL and no drug release above 30% DL. It was observed that formation of discrete drug-rich droplets at lower DLs led to rapid and congruent release of both drug and polymer, whereas formation of continuous drug-rich phase at the ASD matrix-solution interface was the cause of poor release above certain DLs. Thus, the domain size and interconnectivity of phase separated drug-rich domains appear to be critical factors impacting drug release from RTV-PVPVPA ASDs.     

Development of Solid Dispersion by Hot Melt Extrusion Using Mixtures of Polyoxylglycerides With Polymers as Carriers for Increasing Dissolution Rate of a Poorly Soluble Drug Model

Various polyoxylglycerides have been researched extensively in the development of solid dispersions (SDs) for bioavailability enhancement of poorly water-soluble drugs. However, because of their low melting points (40°C-60°C), SDs produced are usually soft and semisolid. The objective of present study was to prepare SDs of a Biopharmaceutical Classification System class II drug, carvedilol, in mixtures of stearoyl polyoxylglycerides (Acconon^® C-50; m.p. ～50°C) with polymers by hot melt extrusion to obtain free-flowing powder upon grinding. Miscibility of carvedilol with Kollidon^® VA64, hydroxypropyl methylcellulose acetate succinate, and Klucel^? EXF was first evaluated by film casting, and Kollidon^® VA64 was selected for further study. SDs containing 5%-20% carvedilol, 0%-20% Acconon^® C-50, and the remaining Kollidon^® VA64 were prepared for hot melt extrusion. SDs were characterized by differential scanning calorimetry and powder X-ray diffraction analysis, and dissolution tests were conducted in 250 mL of pH 6.8 phosphate buffer by filling powders in capsules. Carvedilol was miscible with all polymers tested up to 50% and remained amorphous in SDs. The drug release from formulations containing 20% carvedilol and 0, 5%, 10%, and 20% Acconon^® C-50 were 30%, 30%, 70%, and 90%, respectively, in 60 min. SDs containing carvedilol and Acconon^® C-50, up to 20% each, as well as Kollidon^® VA64, were physically stable after 3 months of storage at 25°C/60% relative humidity.     

介孔二氧化硅微球的制备及用于吲哚美辛载药与溶出性质

目的制备介孔二氧化硅微球,以期提高吲哚美辛的溶出速率。方法以表面活性剂十六烷基三甲基溴化铵和普兰尼克三嵌段共聚物P123作为双模板,用软膜板法制备具有介孔孔道的介孔二氧化硅微球药物载体,采用扫描电镜及氮气吸附-脱附手段表征载体形貌、比表面积及孔径分布。用吸附平衡挥干法载药制得吲哚美辛固体分散体,并对该固体分散体的溶出性质进行研究。结果制得的介孔二氧化硅载体由粒径相对均一的球形粒子组成。其粒径主要集中在2～5μm,载体的比表面积为502.87 m²·g2·g^(-1),孔容为2.23 cm(-1),孔容为2.23 cm³·g3·g^(-1),孔径为23.75 nm。吲哚美辛/介孔二氧化硅固体分散体的药物溶出速率与累积溶出度与吲哚美辛原料药相比均有了显著提高。结论吲哚美辛已高度分散于微球载体中,药物的溶出速率明显加快,为提高吲哚美辛生物利用度的研究打下了基础。     

Microwave Synthesis of Nanostructured Functionalized Polylactic Acid (nfPLA) for Incorporation Into a Drug Crystals to Enhance Their Dissolution

Active pharmaceutical ingredients that have low aqueous solubility pose a challenge in the field of drug delivery. In this paper we report for the first time the synthesis of nano-structured, hydrophilized polylactic acid (nfPLA) and its application in the delivery of low solubility drugs. Microwave induced acid oxidation was used to generate nfPLA where the oxygen concentration increased from 27.0 percent to 41.0 percent. Also, the original non dispersible PLA was converted to a relatively dispersible form with an average particle size of 131.4 nm and a zeta potential of -23.3 mV. Small quantities of the nfPLA were incorporated into the crystals (0.5 to 2.0 % by weight) of a highly hydrophobic, low solubility antifungal drug Griseofulvin (GF) to form a composite (GF-nfPLA). An antisolvent approach was used for the synthesis of the drug composite. SEM and Raman imaging showed non-uniform distribution of the nfPLA on the crystal surface. The solubility of GF increased from 8.89 µg/mL to as high as 49.67 µg/mL for the GF-nfPLA. At the same time zeta potential changed from -15.4 mV to -39.0 mV, therefore the latter was a relatively stable colloid. Octanol-water partitioning also showed a similar effect as logP reduced from 2.16 for pure GF to 0.55 for GF-nfPLA. In vitro dissolution testing showed six times higher aqueous solubility of GF-nfPLA compared to pure GF. The time for 50 (T₅₀) and 80 % (T₈₀) dissolution reduced significantly for the nfPLA composites; T₅₀ reduced from 40.0 to 14.0 min and T₈₀ reduced form unachievable to 47.0 min. Overall, the PLA which is an FDA approved, bioabsorbable polymer can be used to enhance the dissolution of hydrophobic pharmaceuticals and this can lead to higher efficacy and lower the required dosage for drugs.     

Supersaturation,nucleation, and crystal growth during single- and biphasic dissolution of amorphous solid dispersions: Polymer effects and implications for oral bioavailability enhancement of poorly water soluble drugs

The influence of polymers on the dissolution, supersaturation, crystallization, and partitioning of poorly water soluble compounds in biphasic media was evaluated. Amorphous solid dispersions (ASDs) containing felodipine (FLD) and itraconazole (ITZ) were prepared by hot melt mixing (HMM) using various polymers. The ASDs were analyzed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and HPLC. Amorphous drug conversion was confirmed using DSC and PXRD, and drug stability by HPLC. Single- and biphasic dissolution studies of the ASDs with concurrent dynamic light scattering (DLS) and polarized light microscopic (PLM) analysis of precipitated drugs were performed. HPLC revealed no HMM-induced drug degradation. Maximum partitioning into the organic phase was dependent upon the degree of supersaturation. Although the highest supersaturation of FLD was attained using Eudragit® EPO and AQOAT® AS-LF with better nucleation and crystal growth inhibition using the latter, higher partitioning of the drug into the organic phase was achieved using Pharmacoat® 603 and Kollidon® VA-64 by maintaining supersaturation below critical nucleation. Critical supersaturation for ITZ was surpassed using all of the polymers, and partitioning was dependent upon nucleation and crystal growth inhibition in the order of Pharmacoat® 603 > Eudragit® L-100-55 > AQOAT® AS-LF. HMM drug-polymer systems that prevent drug nucleation by staying below critical supersaturation are more effective for partitioning than those that achieve the highest supersaturation.     

Mechanistic Study of Belinostat Oral Absorption From Spray-Dried Dispersions

Spray-dried dispersions (SDDs) are an important technology for enhancing the oral bioavailability of poorly water-soluble drugs. To design an effective oral SDD formulation, the key rate-determining step(s) for oral drug absorption must be understood. This work combined in vivo and in vitro tests with in silico modeling to identify the rate-determining steps for oral absorption of belinostat SDDs made with 3 different polymers (PVP K30, PVP VA64, and HPMCAS-M). The goal was developing a belinostat SDD formulation that maximizes oral bioavailability (ideally matching the performance of a belinostat oral solution) and defining critical performance attributes for formulation optimization. The in vivo pharmacokinetic study with beagle dogs demonstrated that 1 of the 3 SDDs (PVP K30 SDD) matched the performance of the oral solution. In vitro data coupled with in silico modeling elucidated differences among the SDDs and supported the hypothesis that absorption of belinostat in the small intestine from the other 2 SDDs (PVP VA64 and HPMCAS-M) may be limited by dissolution rate or reduced drug activity (maximum concentration) in the presence of polymer. It was concluded that drug concentration in the stomach before emptying into the proximal intestine is a key factor for maximizing in vivo performance.     

Development,characterization and solubility enhancement of comparative dissolution study of second generation of solid dispersions and microspheres for poorly water soluble drug

The poor dissolution characteristics of water-insoluble drugs are a major challenge for pharmaceutical scientists. Reduction of the particle size/increase in the surface area of the drug is a widely used and relatively simple method for increasing dissolution rates. The objective of this study was to improve solubility, release and comparability of dissolution of a poorly soluble drug using two different types of formulations (solid dispersions and microspheres). Hydrochlorothiazide was used as a model drug. The solid dispersions and microspheres were prepared by solvent evaporation method using ethyl cellulose, hydroxypropyl methylcellulose in different drug-to-carrier ratios (1:1, 1:2 w:w). The prepared formulations were evaluated for interaction study by Fourier transform infrared spectroscopy, differential scanning calorimetry, percentage of practical yield, drug loading, surface morphology by scanning electron microscopy, optical microscopy and in-vitro release studies. The results showed no interaction between the drug and polymer, amorphous state of solid dispersions and microspheres, percentage yield of 42.53% to 78.10%, drug content of 99.60 % to 99.64%, good spherical appearance in formulation VI and significant increase in the dissolution rate.     

In-vitro studies of enteric coated diclofenac sodium-carboxymethylcellulose microspheres

Abstract

Microspheres containing diclofenac sodium (DS) were prepared using carboxy-methylcellulose (CMC) as the main support material (1·0, 2·0, 3·0% (w/v)) and aluminium chloride as the crosslinker. Drug to polymer ratios of 1:1, 1:2 and 1:4 were used to obtain a range of microspheres. The microspheres were then coated with an enteric coating material, Eudragit®S-100, with aqueous solution concentrations of 10 and 20% (w/v). Encapsulation efficiency, % yield value, particle sizes and in-vitro dissolution behaviour were investigated. The surface of the enteric coated microspheres seemed to be all covered with Eudragit®S-100 from scanning electron microscopy observation. It was also observed that increasing the CMC concentration led to an increase in the encapsulation efficiency, % yield value and particle size and decreased the release rate. Eudragit®S-100 coating did not significantly alter the size but the release rate was significantly lower even when the lower concentration solution was used.     

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.