Comparison of the relative stability of pharmaceutical cocrystals consisting of paracetamol and dicarboxylic acids

Objective: The aim of this study is to evaluate the relative stability of pharmaceutical cocrystals consisting of paracetamol (APAP) and oxalic acid (OXA) or maleic acid (MLA).

Significance: These observations of cocrystal stability under various conditions are useful coformer criteria when cocrystals are selected as the active pharmaceutical ingredient in drug development.

Method: The relative stability was determined from the preferentially formed cocrystals under various conditions.

Result: Cocrystal of APAP–OXA was more stable than that of APAP–MLA in a ternary cogrinding system and possessed thermodynamical stability. On the other hand, when grinding with moisture or maintaining at high temperatures and relative humidity conditions, APAP–MLA was more stable, and OXA converted to OXA dihydrate. In the slurry method, APAP–OXA was more stable in aprotic solvents because the APAP–OXA with low-solubility product precipitated.

Conclusions: The relative stability order was affected by preparing conditions of presence of moisture. This order might attribute to the small difference of crystal structure in the extension of the hydrogen bond network.     

Applying the approximation method PAINT and the interactive method NIMBUS to the multiobjective optimization of operating a wastewater treatment plant

Using an interactive multiobjective optimization method called NIMBUS and an approximation method called PAINT, preferable solutions to a five-objective problem of operating a wastewater treatment plant are found. The decision maker giving preference information is an expert in wastewater treatment plant design at the engineering company Pöyry Finland Ltd. The wastewater treatment problem is computationally expensive and requires running a simulator to evaluate the values of the objective functions. This often leads to problems with interactive methods as the decision maker may get frustrated while waiting for new solutions to be computed. Thus, a newly developed PAINT method is used to speed up the iterations of the NIMBUS method. The PAINT method interpolates between a given set of Pareto optimal outcomes and constructs a computationally inexpensive mixed integer linear surrogate problem for the original wastewater treatment problem. With the mixed integer surrogate problem, the time required from the decision maker is comparatively short. In addition, a new IND-NIMBUS^® PAINT module is developed to allow the smooth interoperability of the NIMBUS method and the PAINT method.     

Evaluation of superabsorbent linseed-polysaccharides as a novel stimuli-responsive oral sustained release drug delivery system

Context: Advancement in technology has transformed the conventional dosage forms to intelligent drug delivery systems. Such systems are helpful for targeted and efficient drug delivery with minimum side effects. Drug release from these systems is governed and controlled by external stimuli (pH, enzymes, ions, glucose, etc.). Polymeric biomaterial having stimuli-responsive properties has opened a new area in drug delivery approach.

Objective: Potential of a polysaccharide (rhamnogalacturonan)-based hydrogel from Linseeds (Linum usitatissimum L.) was investigated as an intelligent drug delivery material.

Materials and methods: Different concentrations of Linseed hydrogel (LSH) were used to prepare caffeine and diacerein tablets and further investigated for pH and salt solution-responsive swelling, pH-dependent drug release, and release kinetics. Morphology of tablets was observed using SEM.

Results: LSH tablets exhibited dynamic swelling–deswelling behavior with tendency to swell at pH 7.4 and in deionized water while deswell at pH 1.2, in normal saline and ethanol. Consequently, pH controlled release of the drugs was observed from tablets with lower release (<10%) at pH 1.2 and higher release at pH 6.8 and 7.4. SEM showed elongated channels in swollen then freeze-dried tablets.

Discussion: The drug release was greatly influenced by the amount of LSH in the tablets. Drug release from LSH tablets was governed by the non-Fickian diffusion.

Conclusions: These finding indicates that LSH holds potential to be developed as sustained release material for tablet.     

SeDeM expert system a new innovator tool to develop pharmaceutical forms

Context: The SeDeM expert system is based on the experimental study and quantitative determination of the characterization parameters of powdered substances, the aim being to determine whether a substance is suitable for producing tablets by means of direct compression (DC) technology, thereby reducing the lead time for pre-formulation studies. Additionally, this expert system also provides formulations with a minimum number of excipients.

Objective: We used this system to analyze suitable formulas for the production of orodispersible ibuprofen tablets.

Method: Twenty-one disintegrants and ibuprophen were characterized using SeDeM methodology.

Results: The results indicated that production of ibuprofen tablets by DC would require improvements in the dimension and compressibility factors of the active pharmaceutical ingredient. The expert system analysis provided the specific percentage of disintegrant needed to blend with ibuprofen and a standardized formula of lubricants in order to obtain a powder mix that would successfully produce tablets by DC. The eight formulas proposed by SeDeM were produced and tested in the laboratory.

Conclusion: All eight formulas successfully produced tablets by DC, but only four of them could be considered suitable for use as an orodispersible tablet and accomplishes all the pharmaceutical quality parameters. So, in fact, the use of the SeDeM system reduced the time of medicine’s development and therefore the cost of the activity.     

Enhancing the solubility and masking the bitter taste of propiverine using crystalline complex formation

Context: Patient compliance can be reduced when bitter-tasting compounds, such as propiverine hydrochloride, are administered orally. Propiverine hydrochloride is an example of a drug with a bitter taste, used for the treatment of overactive bladders.

Objective: This study tested whether propiverine free base palatability and aqueous solubility could be improved by crystalline complex formation.

Materials and methods: We used 42 compounds, and found 9 new propiverine crystalline complexes. The properties and solubility of these complexes were studied using a range of techniques. A taste perception study was carried out using a taste sensor to evaluate the taste masking ability of the crystalline complex formation.

Results: The melting points of the crystalline complexes were higher than that of propiverine. The dissolution rates of the crystalline complexes in aqueous buffer solution (pH 6.8) and in purified water were much faster than that of propiverine. Propiverine salicylic acid crystalline complex had substantially less bitterness than propiverine hydrochloride, which was extremely bitter.

Discussion: The present findings indicated that crystalline complex formation provided an effective approach to enhancing propiverine solubility, and to masking its bitter taste.

Conclusion: Crystalline complex formation represents a useful and valuable technique for the preparation of orally disintegrating tablets and improving patient compliance, even for substances with bitter tastes.     

Development of a Raman method to follow the evolution of coating thickness of pellets

Context: Although several methods have been investigated to measure the film thickness of tablets and its correlation with the dissolution behavior, much fewer such investigations exist for pharmaceutical pellets.

Objective: To study the possibility of measuring the film thickness and predicting the dissolution behavior of pellets produced in different fluid bed equipments with Raman spectroscopy.

Materials and methods: Pyridoxine hydrochloride-layered pellets were produced and coated in two different Strea-1 equipments. Raman spectra were collected and analysed to set up a calibration model based on the film thickness data calculated from Camsizer analysis results. Dissolution tests were done according to Ph. Eur. standards.

Results: Raman spectroscopy proved to be a good tool in the measurement of film thickness. Polymer weight gain showed a linear correlation with film thickness but was a poor predictor of dissolution results below a threshold value.

Conclusion: The Raman spectroscopic measurement of a small sample can provide accurate data of the film thickness. The investigation suggests that a threshold value might exist for the film thickness above which it can be used to judge future dissolution results.     

Mechanical and electrical properties of electrospun CNT/PVDF nanofiber for micro-actuator applications

Electrospun polyvinylidene fluoride (PVDF)-containing carbon nanotubes (CNT) were prepared for use in fabricating actuator materials. Actuating displacement was measured in an electrochemical environment. The electrospun nanofibers were arranged using a drum-type collector, and morphology was investigated using a field emission-scanning electron microscope. The uniformity of dispersion of CNT in the PVDF nanofibers was monitored by electron probe X-ray micro-analysis. Tensile strength and electrical resistivity results were used as an indication of the state of alignment. The electrospun CNT/PVDF nanofiber sheets exhibited better mechanical and electrical properties in the arranged direction. The efficiency and electrical capacities of electrospun CNT/PVDF nanofiber sheet were compared with those of cast PVDF sheets for use in actuator applications in electrochemical environments. The electrospun CNT/PVDF nanofiber sheets exhibited much better actuator performance than PVDF sheets, which are attributed to their superior electrical properties.

Highlights

(1) The interfacial durability of CNT/PVDF nanofibers was enhanced to increase contact area by reinforcing CNT.

(2) The efficiency of CNT/PVDF actuators was improved due to interfacial properties.

(3) Thin thickness drum-type collector was made to enhance nanofiber alignment.

(4) The arranged CNT/PVDF nanofibers exhibited better mechanical and actuating displacements.     

Aloin delivery on buccal mucosa: ex vivo studies and design of a new locoregional dosing system

Context: Chemoprevention of potential malignant disorders or cancerous lesions that affect oral mucosae requires extended duration of treatment. Locoregional delivery of natural products could represent a promising strategy for this purpose.

Objective: To investigate the aptitude of aloin to permeate through, or accumulate in, the buccal mucosa and to develop a new prolonged oro-mucosal drug delivery system.

Materials and methods: Permeation/accumulation of aloin from Curacao Aloe (containing 50% barbaloin) was evaluated ex vivo, using porcine buccal mucosa as the most useful model to simulate human epithelium. Oro-mucosal matrix tablets were prepared by dispersing aloin (10% w/w) in Eudragit® RS 100 as, biocompatible, low permeable, pH-independent, and non-swelling polymer. The prepared tablets were evaluated for drug–polymer compatibility, weight variation, drug uniformity content, diameter, thickness, hardness, friability, swelling, mucoadhesive strength, and drug release.

Results: Aloin has low tendency to cross buccal mucosa, permeation is marginal, and high drug amounts remain entrapped into the epithelium. Matrix tablets characteristics were in agreement with pharmacopoeial requirements. Drug release showed highly reproducible Higuchian profile. Delivery through matrix tablets promoted drug accumulation in the mucosal tissue.

Discussion and conclusion: Following application of matrix tablets on porcine buccal mucosa, the amount of discharged drug recovered in the tissue should be sufficient to produce the desired effects, providing therapeutic drug levels directly at the site of action. Aloin-loaded tablets are valid candidates for prevention/treatment of potentially malignant disorders and oral cancer and could potentially lead to clinically relevant drug delivery system as coadjuvant of conventional chemotherapy/radiation therapy.     

Lubricant sensitivity in function of paddle movement in the forced feeder of a high-speed tablet press

Context: The negative impact of magnesium stearate (MgSt) on the hardness of tablets is a well-known phenomenon, but the influence of paddle movement in the forced feeder on the lubricant effect during tablet compression is often neglected.

Objective: The purpose of this research was to investigate the influence of paddle speed in the forced feeder on tablet tensile strength (TS).

Materials and methods: Mixtures of microcrystalline cellulose (MCC) and MgSt (0.5%) were blended using different methods (low & high shear). After blending, the formulations were compressed into tablets. All parameters of the tableting cycle were kept constant except the speed of the paddles in the forced feeder.

Results and discussion: The blending technique affected the sensitivity of the formulation to the paddle speed. The TS of pure MCC tablets did not change in function of paddle speed, while tablets prepared by low shear mixing became softer at higher paddle speed. The TS of tablets manufactured using the high-shear mixed blend was low and did not vary in function of paddle speed, suggesting that overlubrication already occurred during the initial blending step. Furthermore, analysis of the machine parameters allowed evaluation of the influence of the paddles on the flowability, initial packing, and compactability of the powder mixtures.

Conclusion: The results elucidated that during manufacturing of tablets using MgSt-containing blends care should not only be taken during the blending step prior to tableting, but also during the tableting process itself, as paddle speed can affect tablet TS, a critical quality attribute.     

Development of optimized self-nanoemulsifying lyophilized tablets (SNELTs) to improve finasteride clinical pharmacokinetic behavior

Objective: Preparation of an optimized finasteride (FSD) lyophilized tablets loaded with self-nanoemulsifying drug delivery system (SNEDDS).

Significance: Enhance FSD bioavailability in male pattern baldness and benign prostatic hyperplasia.

Methods: Two-step optimization was implemented to achieve the study goals. First; the mixture design was used to develop an optimized SNEDDS through which the effect of cosurfactant number of carbon atoms on SNEDDS particle size and thermodynamic stability has been tested. Second; the different tablet excipients have been used to develop an optimized self-nanoemulsifying lyophilized tablets (SNELTs). The prepared tablets have been fully characterized. Interaction among tablet components has been studied. Finally, FSD clinical pharmacokinetic has been investigated on human volunteers.

Results: Anise oil and tween 80 were selected as oily phase and surfactant, respectively while different aliphatic alcohols were studied as cosurfactants. Percentages of oil, surfactant, and cosurfactants were significantly affecting SNEDDS particle size. Increasing cosurfactant number of carbon atoms achieved smaller particle size and higher stability. The optimized SNEDDS was found to contain 10.3455, 45.8972, and 43.7573% of anise oil, tween 80, and butanol, respectively. Variations in FSD cumulative release and disintegration time, from the prepared tablets, were attributed to change in the percent of plasdone XL, Avicel and silica. No interaction among components was noticed. Clinical pharmacokinetics illustrated significant enhancement in the studied parameters from the optimized lyophilized tablets loaded with drug SNEDDS when compared to marketed FSD product.

Conclusion: Lyophilized tablets could be considered as a good alternative for conventional solid dosage forms especially when loaded with drug nanosystems.     

Investigations on the transfer of porphyrin from o/w emulsion droplets to liposomes with two different methods

Context: Due to their small particle size, colloidal fat emulsions are suitable for intravenous administration. In order to obtain information on their potential in vivo performance, it is important to find a simple and effective in vitro assay to evaluate the drug release behavior of such particles.

Objective: Two in vitro methods were studied to measure the transfer of a lipophilic model drug from colloidal o/w emulsion droplets (donor) to liposomes (acceptor), which serve as model membranes mimicking cell membranes in the body. In the first method (column method) the acceptor particles were neutral unilamellar vesicles. In the second method (MLV method), multilamellar vesicles (MLV) were used as acceptor.

Materials and methods: The donor nanoemulsions were prepared by high pressure homogenization. Z-average particle size, polydispersity index and zeta potential were determined.

Results: The transfer of porphyrin was moderate to the acceptor MLV and rapid to the acceptor unilamellar vesicles. The amount of transferred porphyrin at the end of the experiment depended on the transfer method and the donor/acceptor ratio. With both acceptors the transfer of porphyrin stopped at a concentration lower than the theoretical equilibrium values.

Discussion: Many factors such as acceptor particle size and donor to acceptor lipid molar ratio affect the drug transfer from the donor particles to the different acceptors.

Conclusion: Both methods seem to be suitable to study the drug transfer from such colloidal emulsion and the use of lipophilic acceptor particles is a better approach to the conditions in blood.     

A study of photostability and compatibility of the anti-chagas drug Benznidazole with pharmaceutics excipients

Context: Benznidazole (BNZ) is an antiparasitic with trypanocidal properties for the etiological treatment of Chagas disease since 1973. Monitoring the stability of this drug is one of the most effective methods of assessment, forecasting and prevention of problems related to quality product.

Objective: To investigate the direct and indirect photodegradation of BNZ and to evaluate the interference of the excipients used in the forms dosage solid as well as to shed light on the chemical structure of the degradation products obtained.

Materials and methods: To perform this work we adopted the “ICH Harmonised Tripartite Guideline: Photostability Testing of New Drug Substances and Products Q1B” (Guideline Q1B). We used benzonidazole (BNZ) (N-benzil-2-(2-nitroimidazol-1-il) acetamide) (LAFEPE®, Recife, Brazil) and various excipients; beyond high-performance liquid chromatography (HPLC), differential scanning calorimetry (DSC), infrared spectroscopy (IR) and mass spectrometry/mass spectrometry (MS/MS). The indirect photodegradation of BNZ was carried out using physical mixtures with 13 pharmaceutical excipients commonly used in the preparation of solid dosage forms.

Results: HPLC and MS/MS techniques were selected for the identification of two photoproducts (PPs) and photoreactions found in direct and indirect tests with the microcrystalline cellulose, considered a critical excipient.

Discussion: Despite variations in the infrared spectrometry, differential scanning calorimetry and differential thermogravimetry curves, these techniques are not conclusive since the study of photodegradation of the drug caused decay of 30%, according to the ICH.

Conclusions: The results show that BNZ only undergoes direct photodegradation, since no new PPs were found for a combination of the drug and excipients.     

Reduction of tablet weight variability by optimizing paddle speed in the forced feeder of a high-speed rotary tablet press

Context: Tableting is a complex process due to the large number of process parameters that can be varied. Knowledge and understanding of the influence of these parameters on the final product quality is of great importance for the industry, allowing economic efficiency and parametric release.

Objective: The aim of this study was to investigate the influence of paddle speeds and fill depth at different tableting speeds on the weight and weight variability of tablets.

Materials and methods: Two excipients possessing different flow behavior, microcrystalline cellulose (MCC) and dibasic calcium phosphate dihydrate (DCP), were selected as model powders. Tablets were manufactured via a high-speed rotary tablet press using design of experiments (DoE). During each experiment also the volume of powder in the forced feeder was measured.

Results and discussion: Analysis of the DoE revealed that paddle speeds are of minor importance for tablet weight but significantly affect volume of powder inside the feeder in case of powders with excellent flowability (DCP). The opposite effect of paddle speed was observed for fairly flowing powders (MCC). Tableting speed played a role in weight and weight variability, whereas changing fill depth exclusively influenced tablet weight.

Conclusion: The DoE approach allowed predicting the optimum combination of process parameters leading to minimum tablet weight variability. Monte Carlo simulations allowed assessing the probability to exceed the acceptable response limits if factor settings were varied around their optimum. This multi-dimensional combination and interaction of input variables leading to response criteria with acceptable probability reflected the design space.     

Determining osmotic pressure of drug solutions by air humidity in equilibrium method

Objective: To establish a new osmotic pressure measuring method with a wide measuring range.

Method: The osmotic pressure of drug solutions is determined by measuring the relative air humidity in equilibrium with the solution. The freezing point osmometry is used as a control.

Results: The data obtained by the proposed method are comparable to those by the control method, and the measuring range of the proposed method is significantly wider than that of the control method.

Conclusion: The proposed method is performed in an isothermal and equilibrium state, so it overcomes the defects of the freezing point and dew point osmometries which result from the heterothermal process in the measurement, and therefore is not limited to diluted solutions.     

Optimization of the Ussing chamber setup with excised rat intestinal segments for dissolution/permeation experiments of poorly soluble drugs

Context: Prediction of the in vivo absorption of poorly soluble drugs may require simultaneous dissolution/permeation experiments. In vivo predictive media have been modified for permeation experiments with Caco-2 cells, but not for excised rat intestinal segments.

Objective: The present study aimed at improving the setup of dissolution/permeation experiments with excised rat intestinal segments by assessing suitable donor and receiver media.

Methods: The regional compatibility of rat intestine in Ussing chambers with modified Fasted and Fed State Simulated Intestinal Fluids (Fa/FeSSIF_mod) as donor media was evaluated via several parameters that reflect the viability of the excised intestinal segments. Receiver media that establish sink conditions were investigated for their foaming potential and toxicity. Dissolution/permeation experiments with the optimized conditions were then tested for two particle sizes of the BCS class II drug aprepitant.

Results: Fa/FeSSIF_mod were toxic for excised rat ileal sheets but not duodenal sheets, the compatibility with jejunal segments depended on the bile salt concentration. A non-foaming receiver medium containing bovine serum albumin (BSA) and Antifoam B was nontoxic. With these conditions, the permeation of nanosized aprepitant was higher than of the unmilled drug formulations.

Discussion: The compatibility of Fa/FeSSIF_mod depends on the excised intestinal region. The chosen conditions enable dissolution/permeation experiments with excised rat duodenal segments. The experiments correctly predicted the superior permeation of nanosized over unmilled aprepitant that is observed in vivo.

Conclusion: The optimized setup uses FaSSIF_mod as donor medium, excised rat duodenal sheets as permeation membrane and a receiver medium containing BSA and Antifoam B.     

Processing of pharmaceutical materials by electrospraying under reduced pressure

Context: Electrospraying was used in drug particle production.

Objective: The aim of the research was to evaluate the possibilities to produce drug particles with desired pharmaceutical properties by electrospraying. In particular, the effect of drying pressure on particle properties was studied.

Materials and methods: A poorly water soluble model drug (budesonide) was dissolved in chloroform, and the solution was atomized by electrospraying. Following this, the charged droplets were neutralized and dried in a drying chamber. The pressure in the drying chamber was varied. The dried particles were collected and analyzed.

Results: The pressure reduction had a slight impact on particle size distribution. The particles produced in reduced pressure turned out to be notably more porous than the particles produced in atmospheric pressure. The pressure reduction also affects the degree of crystallinity of the product. The dissolution of the particles produced in reduced pressures was faster to a certain extent than that of the particles produced in atmospheric pressure.

Discussion and conclusions: A setup for electrospraying materials in a reduced pressure was presented. The pressure reduction had a notable impact on particle morphology. The possibilities to tailor the particle properties during electrospraying were studied.     

Potential technique for tiny crystalline detection in lycopene-loaded SLN and NLC development

Context: The advantage of solid nanocarriers like solid lipid nanoparticles (SLN) or nanostructured lipid carriers (NLC) is related to some degree of crystalline characteristics of the lipid. However, the detection of tiny content of crystalline structure in such nanoparticles is difficult.

Objective: The aim of this study was to explore a potential method for detection of low degree of crystalline characteristics of lycopene-loaded SLN and NLC.

Methods: Crystalline characteristics investigation was done by polarized light microscope (PLM), differential scanning calorimeter (DSC), X-ray diffractometer (XRD) and transmission electron microscope (TEM).

Results and discussion: It was found that high crystalline characteristics as anisotropic molecular organization crystal of pure orange wax and lycopene could be investigated by PLM, DSC and WAXS. Low crystallinity of lycopene-loaded SLN and NLC could not be detected by those techniques. Electron diffraction mode of TEM showed potential detection of tiny crystalline characteristics of such systems. The diffraction pattern of lycopene-loaded SLN and NLC exhibited obvious zero order laue zone indicating an isotropic fine grained polycrystalline of the nanoparticles.

Conclusion: It could be concluded that TEM is a promising method for detection of low-level crystallinity of solid nanocarriers.     

Ultrasound-assisted preparation of novel ibuprofen-loaded excipient with improved compression and dissolution properties

Context: Most of the active pharmaceutical ingredients (APIs) suffer from a drawback of poor aqueous solubility. In addition to the same, some APIs show poor tabletting behavior creating problems in formulation development. Crystal engineering can be an efficient tool in rectification of such problems associated with the APIs. Thus present work deals with crystallization of ibuprofen (a model drug) onto the surface of dicalcium phosphate (DCP) particles using different techniques.

Objective: The objective of the present work was to prepare ibuprofen-loaded DCP particles and further to analyze them for compressibility and dissolution behavior.

Materials and methods: Various crystallization techniques such as solvent evaporation (SE), melt crystallization (MC), melt sonocrystallization (MSC), antisolvent crystallization (AC), and antisolvent sonocrystallization (ASC) were screened for the preparation of ibuprofen-loaded DCP. Products obtained from different techniques were analyzed for physicochemical, micromeritic and compression properties.

Results and discussion: ASC technique was found to be suitable for preparing directly compressible ibuprofen-loaded DCP particles. The change in the crystal habit (needle to plate shape) of ibuprofen and its crystallization in miniscular form onto the surface of DCP particles showed significant improvement in the dissolution rate and compression properties of ibuprofen due to an increase in specific surface area when compared with ibuprofen crystallized by other techniques. Additionally, the tablets prepared from ASC powder did not require binder since ibuprofen acted as melt binder during compression.

Conclusion: Directly compressible ibuprofen-loaded DCP particles can serve as an alternative for conventional ibuprofen tablets prepared by wet granulation technique.     

Physical barrier type abuse-deterrent formulations: monitoring sintering-induced microstructural changes in polyethylene oxide placebo tablets by near infrared spectroscopy (NIRS)

Objective: The monitoring and evaluation of sintering-induced tablet strength of a polyethylene oxide (PEO) based placebo tables was accomplished using infrared spectroscopy (NIRS).

Significance: Evaluation of high molecular weight PEO-based tablet matrices for abuse deterrent formulation applications is an analytical challenge. NIRS is one tool that can provide physical and chemical evaluation of this polymer and tablet system. In addition, the use of NIRS as a process analytical tool (PAT) to monitor oven sintering of pharmaceutical tablets has not been recorded in the literature. The multiplicative scattering correction (MSC) algorithm was also successfully applied as a new and fast way to calculate NIRS spectral slopes and intercepts to build models against tablet tensile strength with respect to sinter time.

Methods: Both spectral slope regression (SSR) and spectral intercept regression (SIR) models were compared to commonly used partial least squares analysis (PLS) to evaluate placebo PEO based pharmaceutical tablets comprised of PEO at 70, 50, 30% w/w that were compressed at two solid fraction (SF) levels.

Results: All three regression techniques, PLS, SSR, SIR, were evaluated for robustness and reliability and physical relevancy to the system studied. The methods were ranked in utility with SSR being the best method followed by SIR then PLS.

Conclusions: The MSC algorithm was presented to quickly calculate spectral slopes and intercepts for use in SSR and SIR analysis. SSR models were successfully applied and assessed as the optimal modeling technique to monitor sintering of PEO-based matrix tablets.     

RGD peptide targeted lipid-coated nanoparticles for combinatorial delivery of sorafenib and quercetin against hepatocellular carcinoma

Context: Combination therapies provide a potential solution to address the tumor heterogeneity and drug resistance issues by taking advantage of distinct mechanisms of action of the multiple therapeutics.

Objective: To design arginine-glycineaspartic acid (RGD) modified lipid-coated nanoparticles (NPs) for the co-delivery of the hydrophobic drugs against hepatocellular carcinoma (HCC).

Materials and methods: RGD modified lipid-coated PLGA NPs were developed for the targeted delivery of both sorafenib (SRF) and quercetin (QT) (RGD-SRF-QT NPs). Chemical–physical characteristics and release profiles were evaluated. In vitro cell viability assays were carried out on HCC cells. In vivo antitumor efficacies were evaluated in HCC animal model.

Results and discussion: The combination of SRF and QT formulations was more effective than the single drug formulations in both NPs and solution groups. RGD-SRF-QT NPs achieved the most significant tumor growth inhibition effect in vitro and in vivo.

Conclusion: The resulting NPs could provide a promising platform for co-delivery of multiple anticancer drugs for achievement of combinational therapy and could offer potential for enhancing the therapeutic efficacy on HCC.