In vitro-in vivo evaluation of supercritical processed solid dispersions: permeability and viability assessment in Caco-2 cells

In this study improvement in the bioavailability of carbamazepine (CBZ) prepared as solid dispersions by conventional solvent evaporation and supercritical fluid (SCF) processing methods was assessed, along with the elucidation of the mechanism of improved absorption. Solid dispersions of CBZ in polyethylene glycol (PEG) with either Gelucire 44/14 or vitamin E-TPGS (TPGS) were evaluated by intrinsic dissolution. Directional transport through Caco-2 cell monolayers was determined in the presence and absence of TPGS. Cell viability in presence of various concentrations of amphiphilic carriers was seen. In vivo oral bioavailability was determined in rats. The apparent intrinsic dissolution rates (IDR) of both conventional- and SCF-CBZ/PEG 8000/TPGS solid dispersions were increased by 13- and 10.6-fold, respectively, relative to neat CBZ. CBZ was not a substrate of P-glycoprotein. Higher CBZ permeability was seen in presence of 0.1% TPGS. Cell viability studies showed significant cytotoxicity only at or above 0.1% amphiphilic carrier. Supercritical treated formulation (without amphiphilic carrier) displayed oral bioavailability on par with those conventional solid dispersions augmented with amphiphilic carriers. An in vitro-in vivo correlation was seen between IDR and the AUC of the various CBZ solid dispersions. Bioavailability of CBZ was more a function of dissolution as opposed to membrane effects. Although bioavailability from SCF processed dispersions was better than conventionally processed counterparts (except for one formulation containing Gelucire 44/14), an interaction of processing method and inclusion of an amphiphilic carrier, rather by one factor alone contributed to optimal absorption, thus giving contradictory results for Gelucire 44/14 and TPGS formulations.     

Enhancing the bioavailability of ABT-963 using solid dispersion containing Pluronic F-68

Solid dispersions using Pluronic F-68 as a carrier were studied for improving the dissolution and bioavailability of ABT-963, a poorly water-soluble compound. The solid dispersions were prepared either by evaporation of the ethanol solutions containing ABT-963 and Pluronic, or by cooling the hot melt of the drug in the carrier. The dispersions were characterized using differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy, elemental mapping, and by constructing the melting point phase diagram. In vitro dissolution and in vivo oral bioavailability in fasted dogs were compared for the solid dispersion and a conventional IR capsule formulation. Results showed that, at a composition of approximately 7.5%, ABT-963 formed a eutectic mixture with Pluronic F-68. Both the drug and the polymer were crystalline in the solid dispersion with a wide range of composition of each component. The solid dispersion substantially increased the in vitro dissolution rate of ABT-963. Dosing of the dispersion to fasted dogs resulted in a significant increase of oral bioavailability compared with the conventional IR capsule formulation. These results show that solid dispersion is a promising approach for developing ABT-963 drug products.     

Enhanced bioavailability of a poorly water-soluble weakly basic compound using a combination approach of solubilization agents and precipitation inhibitors: a case study

Poorly water-soluble weakly basic compounds which are solubilized in gastric fluid are likely to precipitate after the solution empties from the stomach into the small intestine, leading to a low oral bioavailability. In this study, we reported an approach of combining solubilization agents and precipitation inhibitors to produce a supersaturated drug concentration and to prolong such a drug concentration for an extended period of time for an optimal absorption, thereby improving oral bioavailability of poorly water-soluble drugs. A weakly basic compound from Johnson and Johnson Pharmaceutical Research and Development was used as a model compound. A parallel microscreening precipitation method using 96-well plates and a TECAN robot was used to assess the precipitation of the tested compound in the simulated gastric fluid (SGF) and the simulated intestinal fluid (SIF), respectively, for lead solubilizing agents and precipitation inhibitors. The precipitation screening results showed vitamin E TPGS was an effective solubilizing agent and Pluronic F127 was a potent precipitation inhibitor for the tested compound. Interestingly, the combination of Pluronic F127 with vitamin E TPGS resulted in a synergistic effect in prolonging compound concentration upon dilution in SIF. In addition, HPMC E5 and Eudragit L100-55 were found to be effective precipitation inhibitors for the tested compounds in SGF. Furthermore, optimization DOE study results suggested a formulation sweet spot comprising HPMC, Eudragit L 100-55, vitamin E TPGS, and Pluronic F127. The lead formulation maintained the tested compound concentration at 300 μg/mL upon dilution in SIF, and more than 70% of the compound remained solubilized compared with the compound alone at <1 μg/mL of its concentration. Dosing of the solid dosage form predissolved in SGF in dogs resulted in 52% of oral bioavailability compared to 26% for the suspension control, a statistically significant increase (p = 0.002). The enhanced oral bioavailability of the tested compound could be attributed to generation and prolongation of a supersaturated drug concentration in vivo by the solubilizing agents and precipitation inhibitors. The study demonstrates that the combination approach of solubilization agents and precipitation inhibitors provides improved oral bioavailability for a poorly water-soluble weakly basic compound.     

Free flowing solid dispersions of the anti-HIV drug UC 781 with Poloxamer 407 and a maximum amount of TPGS 1000: Investigating the relationship between physicochemical characteristics and dissolution behaviour

Solid dispersions and physical mixtures made up of the poorly water-soluble drug UC 781, a polymer and a surfactant were prepared to contribute to the understanding of the relationship between physicochemical characteristics and dissolution behaviour. In addition, to facilitate downstream processing while still favouring drug dissolution to a maximum extent, formulation conditions were investigated to obtain a free flowing powder which contains a maximum amount of surfactant. Poloxamer 407, a polyethylene-polypropylene glycol block copolymer, was selected as a suitable polymer based on UC 781 supersaturation results. d-Alpha-tocopheryl polyethyleneglycol succinate 1000 (TPGS 1000) was preferred as a surfactant since it increased UC 781 dissolution when formulated in a self-micro emulsifying drug delivery system (SMEDDS), as compared to TPGS 400, TPGS 4000 and TPGS 6000. Based on flow properties, a TPGS 1000/Poloxamer 407 ratio of 80/20 was used to prepare solid dispersions by spray drying. Pure drugs, physical mixtures and solid dispersions were characterized by differential scanning calorimetry and X-ray powder diffraction. Eutectic phase behaviour was obtained in which the relative distribution of the polyethylene glycol folding was dependent on UC 781 concentration. Drug release was markedly increased when formulated as a solid dispersion with Poloxamer 407 and TPGS 1000. Formulation of solid dispersions did however not further improve the drug dissolution rate compared to that of physical mixtures. Nonetheless, variability of dissolution results was considerably reduced upon solid dispersion formulation.     

Pre-clinical and clinical evaluation of solution and soft gelatin capsule formulations for a BCS class 3 compound with atypical physicochemical properties

R1481 is a sub-type selective muscarinic receptor antagonist with the potential treatment of overactive bladder. R1481 presents two challenges for drug development. The first is the viscous semi-solid nature of the active pharmaceutical ingredient (API). The second challenge is the poor oral bioavailability of this water soluble, metabolically stable compound due to low intestinal permeability, and the P-glycoprotein (P-gp) efflux mechanism. Vitamin E TPGS is reported by others to enhance bioavailability by increasing the solubility of active compounds and by inhibiting P-gp in the intestine. In this report, compatibility of R1481 in Capmul MCM-based formulations with and without vitamin E TPGS is summarized. Review of accelerated stability studies of oral formulations led to the identification of a soft gelatin capsule formulation using neat Capmul MCM as an acceptable formulation for Phase 1 clinical studies. Soft gelatin capsules (5 mg strength) were manufactured with and without the addition of vitamin E TPGS. Clinical data show that vitamin E TPGS does not improve systemic exposure of R1481 in humans.     

The use of three different solid dispersion formulations--melt extrusion, film-coated beads, and a glass thermoplastic system--to improve the bioavailability of a novel microsomal triglyceride transfer protein inhibitor

A bioavailable formulation for a water-insoluble microsomal triglyceride transfer protein inhibitor, R103757, was developed using solid dispersion technology. The need for an advanced formulation was tested in the dog by assessing the oral bioavailability of three generic concepts: a tablet (crystalline drug), a capsule (film-coated beads), and an oral solution. These screening studies steered further development in the direction of a solid dispersion. Three solid dispersion platforms were assessed: melt extrusion, film-coated beads, and a glass thermoplastic system. Thermal and spectrophotometric analysis revealed that no crystalline drug was present in any of the formulations. The dissolution profiles of the three dispersion systems showed that release was improved compared with the unmanipulated drug. In addition, stability studies confirmed the physical and chemical integrity of the formulation. A human clinical trial was performed to assess the pharmacokinetics of the three amorphous dispersions. Plasma levels were obtained after single oral administration in both the fasting and fed state. The study indicated that all three approaches improved the bioavailability of R103757 with the glass thermoplastic system providing the best performance. These studies point to the potential usefulness of solid dispersion approaches and expand the possible number of ways to implement these methodologies.     

Development of novel ibuprofen-loaded solid dispersion with enhanced bioavailability using cycloamylose

To develop a novel ibuprofen-loaded solid dispersion with enhanced bioavailability using cycloamylose, it was prepared using spray-drying techniques with cycloamylose at a weight ratio of 1:1. The effect of cycloamylose on aqueous solubility of ibuprofen was investigated. The physicochemical properties of solid dispersions were investigated using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared with ibuprofen powder. This ibuprofen-loaded solid dispersion improved about 14-fold drug solubility. Ibuprofen was present in an unchanged crystalline state, and cycloamylose played the simple role of a solubilizing agent in this solid dispersion. Moreover, the dispersion gave 2-fold higher AUC (area under the drug concentration-time curve) value compared with a ibuprofen powder, indicating that it improved the oral bioavailability of ibuprofen in rats. Thus, the solid dispersion may be useful to deliver ibuprofen with enhanced bioavailability without crystalline change.     

PEGylated γ-tocotrienol isomer of vitamin E: Synthesis,characterization, in vitro cytotoxicity,and oral bioavailability

Vitamin E refers to a family of eight isomers divided into two subgroups, tocopherols and the therapeutically active tocotrienols (T₃). The PEGylated α-tocopherol isomer of vitamin E (vitamin E TPGS) has been extensively investigated for its solubilizing capacity as a nonionic surfactant in various drug delivery systems. Limited information, however, is available about the PEG conjugates of the tocotrienol isomers of vitamin E. In this study two PEGylated γ-T₃ variants with mPEG molecular weights of 350 (γ-T₃PGS 350) and 1000 (γ-T₃PGS 1000) were synthesized by a two-step reaction procedure and characterized by ¹H NMR, HPLC, and mass spectroscopy. The physical properties of their self-assemblies in water were characterized by zeta, CMC, and size analysis. Similar physical properties were found between the PEGylated T₃ and vitamin E TPGS. PEGylated T₃ were also found to retain the in vitro cytotoxic activity of the free T₃ against the MCF-7 and the triple-negative MDA-MB-231 breast cancer cells. PEGylated γ-T₃ also increased the oral bioavailability of γ-T₃ by threefolds when compared to the bioavailability of γ-T₃ formulated into a self-emulsified drug delivery system. No significant differences in biological activity were found between the PEG 350 and 100 conjugates. Results from this study suggest that PEGylation of γ-T₃ represents a viable platform for the oral and parenteral delivery of γ-T₃ for potential use in the prevention of breast cancer.     

Enhanced solubility and bioavailability of flurbiprofen by cycloamylose

The effect of cycloamylose on the aqueous solubility of flurbiprofen was investigated. To improve the solubility and bioavailability of flurbiprofen (poor water solubility), a solid dispersion was spray dried with a solution of flurbiprofen and cycloamylose at a weight ratio of 1:1. The physicochemical properties of solid dispersions were investigated using SEM, DSC, and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared with a commercial product. Cycloamylose increased solubility of flurbiprofen approximately 12-fold and dissolution of it by 2-fold. Flurbiprofen was present in an unchanged crystalline state, and cycloamylose was a solubilizing agent for flurbiprofen in this solid dispersion. Furthermore, the dispersion gave higher AUC and C_max values compared with the commercial product, indicating that it improved the oral bioavailability of flurbiprofen in rats. Thus, the solid dispersion may be useful to deliver flurbiprofen with enhanced bioavailability without changes in crystalline structure.     

Susceptibility to Lipase-Mediated Digestion Reduces the Oral Bioavailability of Danazol After Administration as a Medium-Chain Lipid-Based Microemulsion Formulation

PURPOSE: To investigate the impact of lipidic formulation type on in vitro dispersion and digestion properties and the relationship to oral bioavailability, using danazol as a model lipophilic poorly water-soluble drug. METHODS: Three lipid-based danazol formulations [a long-chain triglyceride solution (LCT-solution) and self-microemulsifying drug delivery systems (SMEDDS) based on long-chain (C18) lipids (LC-SMEDDS) and medium-chain (C8-C10) lipids (MC-SMEDDS)] were administered to fasted beagle dogs and compared with a micronized danazol formulation administered postprandially and in the fasted state. In vitro dispersion and particle size data for the two SMEDDS were compared, and the distribution/solubilization patterns of danazol across the various phases produced during in vitro digestion quantified. RESULTS: The LCT-solution and LC-SMEDDS formulations significantly enhanced the oral bioavailability of danazol when compared to fasted administration of the powder formulation. In contrast, and despite displaying excellent dispersion properties, the MC-SMEDDS resulted in little enhancement in danazol bioavailability. In support of the in vivo findings, in vitro digestion of the medium-chain formulation resulted in significant drug precipitation when compared with the long-chain lipid formulations. CONCLUSIONS: Digestion of microemulsion preconcentrate formulations based on medium-chain lipids may limit in vivo utility when compared with similar formulations based on long chain lipids.     

A novel lipid-based solid dispersion for enhancing oral bioavailability of Lycopene – In vivo evaluation using a pig model

Lycopene is a potent anti-oxidant, which has been widely reported for its potential benefits at reducing the risks of certain types of cancer e.g. prostate cancer. The oral bioavailability of this highly lipophilic carotenoid is low and highly influenced by the extent of intestinal lymphatic uptake. The aim of this study was to develop an optimised formulation, which allows for efficient absorption following oral administration. A self-emulsifying drug delivery system (SEDDS) and solid dispersion of Lycopene were developed initially. Subsequently, a novel lipid based solid dispersion (LBSD) was designed. Processing via a solid dispersion approach was found to alter the solid state characteristics of Lycopene, as determined by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The bioavailability of Lycopene was significantly increased after oral administration of LBSD to fasted pigs, relative to the commercial product (Lycovit^®). A clear distinction in terms of C_max and AUC was observed between Lycovit^® and LBSD. In conclusion, a novel LBSD formulation was developed to enhance the oral bioavailability of the model lipophilic compound, Lycopene, by enhancing dissolution in the gastrointestinal tract and promoting intestinal lymphatic uptake utilising digestible lipid excipients.     

Mechanistic study of solubility enhancement of nifedipine using vitamin E TPGS or solutol HS-15

The objective of our study was to find mechanisms responsible for solubility enhancement of nifedipine in solid dispersions of vitamin E TPGS and/or solutol HS-15. Solid dispersions of nifedipine with selected polymers such as vitamin E TPGS, solutol HS-15, PEG(1,000), and lipocol C-10 of varying drug/polymer ratios were prepared by a fusion method. The solubility enhancement was found to be in the order of vitamin E TPGS > solutol HS-15 > lipocol C-10 > PEG(1,000). Lipocol C-10, with a similar hydrophilic-lipophilic value as vitamin E TPGS, showed a comparable retained solubility enhancement during saturation solubility studies but had lower dissolution profile. Overall, vitamin E TPGS showed the best solubility and dissolution performance, while solutol HS-15 and lipocol C-10 demonstrated moderate solubility enhancements. Solid dispersions of vitamin E TPGS as prepared by microfluidization technique initially showed slightly higher solubility compared with samples prepared by fusion method, but eventually it became the same as the study progressed. However, solid dispersion of solutol HS-15 as prepared by microfluidization demonstrated a significant, sustained increased in solubility over its sample when prepared by fusion method. Based on these results, we concluded that enhanced solubility using vitamin E TPGS and solutol HS-15 resulted from a partial conversion of crystalline drug to the amorphous form, increase in wettability of the drug by water soluble polymers, better separation of drug particles, micellar solubilization of drug by high concentrations of surfactant polymers, and interaction between polymer and drug at the molecular level.     

Recent advances and patents in solid dispersion technology

High lipophilicity and high lattice energy of drugs, which result in poor solubility are major real challenges in the pharmaceutical industry for the successful development and commercialization of suitable dosage forms. Therefore various formulation strategies like complexation, lipid based systems, micronization, nanonization, co-crystals, solid dispersions, solubilization etc. have been investigated to resolve the problems associated with solubility related oral bioavailability of poorly water soluble drugs. This article focuses on solid dispersions which is used as one of the formulation strategies to improve the solubility and bioavailability of BCS class II drugs. The present review discusses the fundamentals of solid dispersions, their formulation techniques including various carriers used, their applications, limitations as well as provide an insight into the various alternative approaches to overcome problems associated with solid dispersions. This review also discusses some important aspects of solid dispersion like phase transition, importance of Tg for solid dispersion, controlled release formulations, IVIVC, and the prospect of innovative solid dispersions. Furthermore, the different patents highlighting the applications of solid dispersions have also been comprehensively discussed in the present review.     

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.     

Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods

This study compares the physicochemical properties of carbamazepine (CBZ) solid dispersions prepared by either a conventional solvent evaporation versus a supercritical fluid process. Solid dispersions of carbamazepine in polyvinylpyrrolidone (PVP) K30 with either Gelucire 44/14 or Vitamin E TPGS, NF (d-alpha-tocopheryl polyethylene glycol 1000 succinate) were prepared and characterized by intrinsic dissolution, differential scanning calorimetry, powder X-ray diffraction and Fourier transform infrared spectroscopy. CBZ/PVP K30 and CBZ/PVP K30/TPGS solid dispersions showed increased dissolution rate. The best intrinsic dissolution rate (IDR) was obtained for supercritically processed CBZ/PVP K30 that was four-fold higher than pure CBZ. Thermograms of various solid dispersions did not show the melting peak of CBZ, indicating that CBZ was in amorphous form inside the carrier system. This was further confirmed by X-ray diffraction studies. Infrared spectroscopic studies showed interaction between CBZ and PVP K30 in solid dispersions. The amorphous state of CBZ coupled with presence of interaction between drug and PVP K30 suggests fewer, if any, stability problems. Because the supercritical-based process produced solid dispersions with IDR better than conventional solid dispersions augmented with amphiphilic carriers, stability issues associated with lipid carriers do not apply, which, in turn, implies easier scale up under current Good Manufacturing Practice for this technique.     

Contribution of formulation and excipients towards enhanced permeation of curcumin

Curcumin (CRM) (CAS number 458-37-07), a naturally-occurring molecule, has diverse pharmacological actions. Recently our research group demonstrated that poor permeability also contributes to its poor oral bioavailability. A self nano-emulsifying drug delivery system (CRM SNEDDS) consisting of Labrasol, Gelucire 44/14, Vitamin E TPGS and PEG 400 was designed and provided 16 times improvement in oral bioavailability in rats, at a dose of 250?mg/kg body weight. Caco-2 cell transport studies were conducted for CRM SNEDDS and CRM in the presence of individual excipients, to determine the extent of improvement in permeability. Papp values for CRM, CRM SNEDDS and CRM in combination with 4 individual excipients were calculated. Transepithelial electrical resistance value was assessed to evaluate the cell morphology and the cellular tight junctions. Permeation of a transcellular marker, Lucifer Yellow was used as a marker to assess monolayer integrity. The tested excipient concentrations were found to be non-toxic to the cell monolayer in 2?h incubation. Results showed that the Papp increased 6.35 times for curcumin in CRM SNEDDS as compared to CRM. Individual excipients enhanced permeation from 1.97 to 6.35 times, with Labrasol showing the highest enhancement of 6.35 times.     

Dissolution enhancement of the anti-HIV drug UC 781 by formulation in a ternary solid dispersion with TPGS 1000 and Eudragit E100

The present research deals with the improvement of the dissolution properties of the anti-HIV drug UC 781. A ternary solid dispersion consisting of a high amount of TPGS 1000 and exhibiting good powder properties with respect to flowability was developed. Eudragit E100 was selected as a polymer based on supersaturation studies. DSC analysis of solid dispersions containing drug doses from 0 to 80% w/w revealed eutectic phase behaviour of the ternary TPGS 100–Eudragit E100–UC 781 mixture. The release of UC 781 in a medium simulating the gastrointestinal lumen was markedly enhanced, reaching a release of 70% w/w after 4 h. XRD results pointed to the presence of crystalline drug in the solid dispersion. The presence of UC 781 in the dispersion had an influence on the TPGS 1000–Eudragit E100 carrier, favoring folding of the polyethylene glycol chains in TPGS 1000. Moreover, the addition of UC 781 to the binary polymer–surfactant mixture was physically expressed by an increase in fluidity of the samples up to a drug load of 50% w/w. NMR was used to investigate this phenomenon, revealing a shielding and/or deshielding effect of the carrier on aromatic C atoms and methyl groups in UC 781. Polyethylene glycol chains present in TPGS 1000 seemed to play a role in this process. In addition, combining UC 781 with the TPGS 1000–Eudragit E100 mixture led to the appearance of TPGS 1000 clusters with a glass transition temperature well below the T_g’s of the pure compounds.     

A conscious dog model for assessing the absorption, enterocyte-based metabolism, and intestinal lymphatic transport of halofantrine.

Postprandial administration of halofantrine (Hf), an important antimalarial, leads to 3- and 12-fold increases in oral bioavailability in humans and beagles, respectively, and corresponding 2.4-fold and 6.8-fold decreases in metabolic conversion to desbutylhalofantrine (Hfm). Factors contributing to the decreased postprandial metabolism of Hf could include inhibition of presystemic CYP3A metabolism by food components and/or recruitment of the intestinal lymphatics as an absorption pathway. Although previous rat studies confirmed Hf base is a substrate for lymphatic transport, it is difficult to extrapolate such data to higher species, as the largely constant bile flow in a rat precludes attainment of representative pre- and postprandial states, and formulations administered to rats are often not relevant to higher species. These limitations have now been addressed by development of a conscious dog model that allows simultaneous study of intestinal lymphatic and nonlymphatic drug absorption and aspects of enterocyte-based drug metabolism. After oral administration of 100 mg Hf base, the mean fasted and postprandial lymphatic transport was 1.3% and 54% of the administered dose, respectively. Comparison of portal and systemic plasma Hfm concentration profiles suggested enterocyte-based conversion of Hf to Hfm; however, the proportion of Hf metabolized to Hfm was similar after fasted or postprandial administration. Hence, it appears that the previously observed decrease in the postprandial metabolism of Hf is largely a consequence of significant postprandial intestinal lymphatic transport (which bypasses first pass hepatic metabolism). This new dog model will facilitate identification of the key factors that impact bioavailability, lymphatic transport, and metabolic profiles of highly lipophilic drugs.     

Processing challenges with solid dosage formulations containing vitamin E TPGS

The objective of this study is to investigate processing challenges associated with the incorporation of Vitamin E TPGS (d-α tocopheryl polyethylene glycol 1000 succinate) into solid pharmaceutical dosage forms. For this work, a wet granulation process (high-shear and fluid bed) was used and Vitamin E TPGS was added as part of the binder solution during granulation. It was shown that Vitamin E TPGS can be incorporated into a prototype formulation at 10% w/w concentration without any significant processing challenges. However, the resulting granulations could only be compressed successfully at low tablet press speeds (dwell time ~100?ms). When compressed at low dwell times (<20?ms) representative of commercial tablet manufacturing, a significant loss in compactability was observed. In addition, several other tablet defects were observed. It was shown that intragranular incorporation of Aeroperl^® 300, a granulated form of colloidal silicon dioxide, was able to overcome these compaction problems. The formulation consisting of Aeroperl^® 300 showed significantly lower granule particle size, higher granule porosity and higher compactability as compared to the formulation without Aeroperl^® 300.     

Solubility and dissolution rate enhancement of lumefantrine using hot melt extrusion technology with physicochemical characterisation

The interest in hot-melt extrusion as a drug delivery technology for the production of solid dispersion is growing rapidly. Lumefantrine (LUMF) is an antimalarial drug that exhibits poor oral bioavailability, in consequence of its poor aqueous solubility. To improve its antimalarial activity, solid dispersion formulation using hot melt extrusion technology was prepared. Appropriate selection of polymers, favoured the production of amorphous LUMF-polymer solid dispersions. The physicochemical properties of solid dispersions were characterized using scanning electron microscope, Infrared spectroscopy, differential scanning calorimetry and X-ray diffraction. LUMF SD showed enhanced dissolution rate attributed to amorphosization of LUMF. The IC50 value of LUMF SD formulations was found to be (0.084–0.213 ng/mL) i.e. 220–101 times lower than the IC50 value of pure LUMF (18.2 ng/mL) and 45–18 times lower than the IC50 value of standard antimalarial drug, chloroquine (3.8 ng/mL). Molecular dynamic simulation approach was used to investigate drug-polymer molecular interaction using computational modelling Schrodinger^® software. LUMF SD powder makes the Coartem^® therapy more operative with value-added beneficial comeback.