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.     

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.     

High throughput research and evaporation rate modeling for solvent screening for ethylcellulose barrier membranes in pharmaceutical applications

Context: Ethylcellulose is commonly dissolved in a solvent or formed into an aqueous dispersion and sprayed onto various dosage forms to form a barrier membrane to provide controlled release in pharmaceutical formulations. Due to the variety of solvents utilized in the pharmaceutical industry and the importance solvent can play on film formation and film strength it is critical to understand how solvent can influence these parameters.

Objective: To systematically study a variety of solvent blends and how these solvent blends influence ethylcellulose film formation, physical and mechanical film properties and solution properties such as clarity and viscosity.

Materials and methods: Using high throughput capabilities and evaporation rate modeling, thirty-one different solvent blends composed of ethanol, isopropanol, acetone, methanol, and/or water were formulated, analyzed for viscosity and clarity, and narrowed down to four solvent blends. Brookfield viscosity, film casting, mechanical film testing and water permeation were also completed.

Results and discussion: High throughput analysis identified isopropanol/water, ethanol, ethanol/water and methanol/acetone/water as solvent blends with unique clarity and viscosity values. Evaporation rate modeling further rank ordered these candidates from excellent to poor interaction with ethylcellulose. Isopropanol/water was identified as the most suitable solvent blend for ethylcellulose due to azeotrope formation during evaporation, which resulted in a solvent-rich phase allowing the ethylcellulose polymer chains to remain maximally extended during film formation. Consequently, the highest clarity and most ductile films were formed.

Conclusion: Employing high throughput capabilities paired with evaporation rate modeling allowed strong predictions between solvent interaction with ethylcellulose and mechanical film properties.     

A novel method for determination of the filling level in the feed frame of a rotary tablet press

Aim: The aim of this study was to investigate whether the filling level within the feed frame of a rotary tablet press can be quantified by laser triangulation combined with the angle recognition of one paddle wheel via rotary encoder.

Significance: Rotary tablet press feed frames are supposed to assure a uniform die filling and, thus, to guarantee the weight and content uniformity of the resulting tablets. Therefore, a constant bulk availability and flow within the feed frame is crucial and has to be ensured by the feed frame design and the operating conditions. So far, there is no instrument available to monitor the bulk filling level or the bulk distribution within feed frames.

Methods: Calcium phosphate dihydrate was used as model powder. The powder surface level was determined via laser triangulation and the angle position of the paddle wheel was monitored via incremental rotary encoder. The data of both parameters was acquired synchronously and evaluated by in-house written software.

Results: Different powder masses led to significantly different filling level signals. The experiments showed a high reproducibility of the determined filling levels. Furthermore, an influence of the rotational speed on the powder distribution was observed.

Conclusions: The developed instrument may be used for quantification of the volumetric filling level within rotary tablet press feed frames. It may either be used to better understand the powder behavior within feed frames or for improvement of the die filling process by implementing the device into a feedback loop.     

Factors influencing the properties and the stability of spray-dried Sennae fructus extracts

Objective: The objective of this study was to characterize the properties of aqueous Sennae fructus extracts prepared by spray-drying at varying process conditions.

Significance: From an industrial point of view it is essential to develop a formulation which has a constant quality over the whole period of its specified shelf-life.

Method: Sennae fructus extracts were spray-dried with different atomizing gas pressures, pump feed rates, and inlet temperatures. The extracts were analyzed for their physical properties and stored at accelerated conditions. Sennoside degradation was monitored by HPLC analysis.

Results: An increase of the atomizing gas pressure had the most pronounced influence on the decrease of moisture content and particle size. An increase of the inlet temperature led to a decrease of moisture content and particle density, as well as an increase of smooth particle amount. An increase in the pump feed rate, increased the moisture content and resulted in stable hollow spheres. The different conditions also led to smooth or wrinkled particle surfaces, and to golfball, donut, and shard particle shapes. The chemical stability of the sennosides differed from each other after storage. Stability-reducing factors were the moisture content of the samples and their hygroscopicities, as well as different particle morphologies. These factors were influenced by the inlet temperature of the spray-drying process. High inlet temperatures led to a positive influence on dryness and particle morphology and therefore on the stability of the sennosides.

Conclusions: Variation of the process conditions affected the resulting particle properties and their storage stability of Sennae fructus extract.     

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.     

Controlled precipitation for enhanced dissolution rate of flurbiprofen: development of rapidly disintegrating tablets

Objective: The aim of this work was to investigate the potential of controlled precipitation of flurbiprofen on solid surface, in the presence or absence of hydrophilic polymers, as a tool for enhanced dissolution rate of the drug. The work was extended to develop rapidly disintegrated tablets.

Significance: This strategy provides simple technique for dissolution enhancement of slowly dissolving drugs with high scaling up potential.

Methods: Aerosil was dispersed in ethanolic solution of flurbiprofen in the presence and absence of hydrophilic polymers. Acidified water was added as antisolvent to produce controlled precipitation. The resultant particles were centrifuged and dried at ambient temperature before monitoring the dissolution pattern. The particles were also subjected to FTIR spectroscopic, X-ray diffraction and thermal analyses.

Results: The FTIR spectroscopy excluded any interaction between flurbiprofen and excipients. The thermal analysis reflected possible change in the crystalline structure and or crystal size of the drug after controlled precipitation in the presence of hydrophilic polymers. This was further confirmed by X-ray diffraction. The modulation in the crystalline structure and size was associated with a significant enhancement in the dissolution rate of flurbiprofen. Optimum formulations were successfully formulated as rapidly disintegrating tablet with subsequent fast dissolution.

Conclusions: Precipitation on a large solid surface area is a promising strategy for enhanced dissolution rate with the presence of hydrophilic polymers during precipitation process improving the efficiency.     

Enhancement of solubility and oral bioavailability of manidipine by formation of ternary solid dispersion with d-α-tocopherol polyethylene glycol 1000 succinate and copovidone

Context: Low bioavailability of oral manidipine (MDP) is due to its low water solubility.

Objective: The objective of this study was to increase the solubility and bioavailability of MDP by fabricating ternary solid dispersion (tSD) with d-α-tocopherol polyethyleneglycol-1000-succinate and copovidone.

Methods: In this study, solid ternary phase diagram was applied in order to check the homogeneity of tSD prepared by melting and solidifying with dry ice. The physicochemical properties of different formulations were determined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR) and hot stage microscopy. Their solubility, dissolution, stability and bioavailability were also investigated.

Results and discussion: The results demonstrated that tSD obtained from ternary phase diagram divided into homogeneous and non-homogeneous regions. In the homogenous region, the transparent characteristics of tSD was observed and considered as a glass solution, which have a higher MDP solubility than that in non-homogenous region. The hot stage microscopy, DSC and PXRD confirmed that solid dispersion was formed in which MDP was molecularly dispersed in the carriers, especially in the homogenous region of phase diagram. FTIR analysis demonstrated strong hydrogen bonding between amine groups of MDP and carbonyl groups of copovidone, which supported a higher solubility and dissolution of tSD. The pharmacokinetic study in Wistar rats showed that the tSD had the greatest effect on oral bioavailability. Immediate hypotensive effect of tSD was also observed in vivo.

Conclusions: The improvement of stability, dissolution and oral bioavailability of MDP could be achieved by using tSD technique.     

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.     

Formulation and development of ophthalmic in situ gel for the treatment ocular inflammation and infection using application of quality by design concept

Context: The conventional liquid ophthalmic delivery systems exhibit short pre-corneal residence time and the relative impermeability to the cornea which leads to poor ocular bioavailability.

Objective: The aim of this study was to apply quality by design (QbD) for development of dexamethasone sodium phosphate (DSP) and tobramycin sulfate (TS)-loaded thermoresponsive ophthalmic in situ gel containing Poloxamer 407 and hydroxyl propyl methyl cellulose (HPMC) K4M for prolonging the pre-corneal residence time, ocular bioavability and decreases the frequency of administration of dosage form. The material attributes and the critical quality attributes (CQA) of the in situ gel were identified. Central composite design (CCD) was adopted to optimize the formulation.

Materials and methods: The ophthalmic in situ forming gels were prepared by cold method. Materials attributes were the amount of Poloxamer 407 and HPMC and CQA identified were Gel strength, mucoadhesive index, gelation temperature and % of drug release of both drug.

Results and discussion: Optimized batch (F*) containing 16.75% poloxamer 407 and 0.54% HPMC K4M were exhibited all results in acceptable limits. Compared with the marketed formulation, optimized in situ gel showed delayed T_max, improved C_max and AUC in rabbit aqueous humor, suggesting the sustained drug release and better corneal penetration and absorption.

Conclusion: According to the study, it could be concluded that DSP and TS would be successfully formulated as in situ gelling mucoadhesive system for the treatment of steroid responsive eye infections with the properties of sustained drug release, prolonged ocular retention and improved corneal penetration.     

A methacrylic hyaluronic acid derivative for potential application in oral treatment of celiac disease

Objective: Aim of this work was the synthesis of a methacrylic hyaluronic acid (HA) derivative and the production, via photocrosslinking, of related hydrogels loaded with an endopeptidase intended for a potential oral treatment of celiac disease.

Methods: The methacrylic derivative of HA was prepared through a one-pot procedure involving the reaction with ethylenediamine (EDA) and methacrylic anhydride (MA). The obtained derivative, named HA-EDA-MA, was used to prepare photocrosslinked hydrogels loaded with a prolyl endopeptidase derived from Flavobacterium meningosepticum (PEP FM) able to detoxify gliadin. Obtained hydrogels were recovered as gels or freeze-dried powders.

Results: Hydrogels obtained as freeze-dried powders, are able to protect loaded enzyme from degradation due to freeze-drying process and from alteration during storage, overall in the presence of a cryoprotectant. All photocrosslinked HA-EDA-MA hydrogels (gels and powders) release PEP FM in simulated intestinal fluid in sustained manner and in active form. HA-EDA-MA hydrogels are nontoxic as demonstrated through in vitro studies on BALB 3T3 cells.

Conclusions: Prepared hydrogels show a potential application for oral treatment of celiac disease thanks to the possibility to release enzymes able to detoxify the gliadin peptide that induces the immunogenic response.     

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.     

In vitro characterization studies of self-microemulsified bosentan systems

Context: Bosentan is a poorly soluble drug and pose challenges in designing of drug delivery systems.

Objective: The objective of this study is to enhance the solubility, dissolution and shelf-life of bosentan by formulating it as S-SMEDDS capsules.

Materials and methods: Solubility of bosentan was tested in various liquid vehicles such as oils (rice bran and sunflower), surfactants (span 20 and tween 80) and co-surfactants (PEG 400 and propylene glycol) and microemulsions were developed. Bosentan was incorporated into appropriate microemulsion systems which were previously identified from pseudo ternary phase diagrams. Bosentan-loaded SMEDDS were evaluated for drug content, drug release, zeta potential, and droplet size. The selected liquid SMEDDS were converted into solid SMEDDS by employing adsorption and melt granulation. Solid SMEDDS were characterized for micromeritics and evaluated for drug content, drug release, and shelf-life.

Results: Isotropic systems R5, R13, S5, and S13 with submicron droplet size had exhibited 85.45, 94.12, 81.67, and 96.64% drug release, respectively. Solid SMEDDS of MR13 and AS13 formulations with rapid reconstitution ability, exhibited 84.85 and 86.74% of on par drug release. The formulations were physicochemically intact for 1.02 and 1.56 years.

Discussion: Liquid SMEDDS composed with PEG400 had displayed optimal characters. Solid SMEDDS had high-dissolution profiles than bosentan due to modification in the crystalline structure of drug upon microemulsification.

Conclusion: Thus, solid SMEDDS addressed the solubility, dissolution, and stability issues of bosentan and becomes an alternate for clinical convenience.     

Co-milled API-lactose systems for inhalation therapy: impact of magnesium stearate on physico-chemical stability and aerosolization performance

Context: Particle micronization for inhalation can impart surface disorder (amorphism) of crystalline structures. This can lead to stability issues upon storage at elevated humidity from recrystallization of the amorphous state, which can subsequently affect the aerosol performance of the dry powder formulation.

Objective: The aim of this study was to investigate the impact of an additive, magnesium stearate (MGST), on the stability and aerosol performance of co-milled active pharmaceutical ingredient (API) with lactose.

Methods: Blends of API-lactose with/without MGST were prepared and co-milled by the jet-mill apparatus. Samples were stored at 50% relative humidity (RH) and 75% RH for 1, 5, and 15 d. Analysis of changes in particle size, agglomerate structure/strength, moisture sorption, and aerosol performance were analyzed by laser diffraction, scanning electron microscopy (SEM), dynamic vapor sorption (DVS), and in-vitro aerodynamic size assessment by impaction.

Results: Co-milled formulation with MGST (5% w/w) led to a reduction in agglomerate size and strength after storage at elevated humidity compared with co-milled formulation without MGST, as observed from SEM and laser diffraction. Hysteresis in the sorption/desorption isotherm was observed in the co-milled sample without MGST, which was likely due to the recrystallization of the amorphous regions of micronized lactose. Deterioration in aerosol performance after storage at elevated humidity was greater for the co-milled samples without MGST, compared with co-milled with MGST.

Conclusion: MGST has been shown to have a significant impact on co-milled dry powder stability after storage at elevated humidity in terms of physico-chemical properties and aerosol performance.     

Salinomycin nanoparticles interfere with tumor cell growth and the tumor microenvironment in an orthotopic model of pancreatic cancer

Aims: Recently, salinomycin (SAL) has been reported to inhibit proliferation and induce apoptosis in various tumors. The aim of this study was to deliver SAL to orthotopic model of pancreatic cancer by the aid of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs).

Methods: The NPs were physico-chemically characterized and evaluated for cytotoxicity on luciferase-transduced AsPC-1 cells in vitro as well as implanted orthotopically into the pancreas of nude mice.

Results: SAL (3.5 mg/kg every other day) blocked tumor growth by 52% compared to the control group after 3 weeks of therapy. Western blotting of tumor protein extracts indicated that SAL treatment leads to up-regulation of E-cadherin, β-catenin, and transforming growth factor beta receptor (TGFβR) expressions in AsPC-1 orthotopic tumor. Noteworthy, immunofluorescence staining of adjacent tumor sections showed that treatment with SAL NPs cause significant apoptosis in the tumor cells rather than the stroma. Further investigations also revealed that TGFβR2 over-expression was induced in stroma cells after treatment with SAL NPs.

Conclusion: These results highlight SAL-loaded PLGA NPs as a promising system for pancreatic cancer treatment, while the mechanistic questions need to be subsequently tested.     

Passive acoustic emissions from particulates in a V-blender

Context: Regulatory agencies are recommending the development of process analytical technologies (PAT) to improve the efficiency and product quality during pharmaceutical manufacturing.

Objective: The objective of the research was to investigate the potential application of passive acoustic emission monitoring of a V-blender.

Materials and methods: Trials were conducted with sugar spheres, lactose or MCC in a V-blender. Vibrations from acoustic emissions were measured using PCB Piezotronics accelerometers with ICP signal conditioners.

Results and discussion: A wavelet filter was applied to the measured acoustic emissions to remove vibrations from the tumbling motion of the V-shell, allowing a focus on information about particle motion and interactions within the V-shell. The ideal sensor location was determined to be the lid of one of the V-shell arms due to the impact of the tumbling particles on the lid and transmission of the vibrations from other particle motion within the V-shell. The amplitude of vibrations increased with particle size due to larger particle momentum before a collision. The fill level and the V-shell scale also influenced the measured vibrations as particle motion was affected which in turn affected momentum. Changes in particle flowability could be detected through variations in the measured acoustic emissions.

Conclusion: The measured vibrations from passive acoustic emissions reflected particle motion and interactions within a V-blender demonstrating potential as a monitoring method.     

Evaluation of the tamper-resistant properties of biphasic immediate-release/extended-release oxycodone/acetaminophen tablets

Context: Abuse potential of extended-release (ER) opioid tablets increases if tampering causes rapid opioid release.

Objective: To evaluate the susceptibility to tampering of biphasic immediate-release (IR)/ER oxycodone (OC)/acetaminophen (APAP) tablets compared with IR OC/APAP tablets.

Materials and methods: IR/ER OC/APAP and IR OC/APAP tablets were tested at room temperature and after heating, freezing and microwaving. Resistance to crushing was tested using manual and powered tools (e.g. spoons, mortar and pestle, blender, coffee grinder). Tampered tablets were tested for suitability for snorting, OC extraction in solvents and ease of drawing into a syringe. Dissolution of IR/ER OC/APAP in gastric fluid with and without ethanol was tested to determine the potential for facilitating precipitous release of opioid from the tablet.

Results: IR/ER OC/APAP tablets were more crush resistant than IR OC/APAP tablets. Heating, freezing and microwaving had no effect on crush resistance of IR/ER OC/APAP tablets. Although a mortar and pestle pulverized IR/ER OC/APAP tablets, upon contact with solvent, the powder formed a thick gel judged unsuitable for absorption through the nasal mucosa and could not be drawn into a syringe. In contrast, powder from crushed IR OC/APAP tablets dissolved readily, was judged suitable for snorting, and was easily drawn into a syringe. Dissolution of IR/ER OC/APAP tablets in gastric fluid was slowed by the addition of ethanol.

Discussion: IR/ER OC/APAP tablets are resistant to crushing and dissolution compared with IR OC/APAP tablets.

Conclusion: IR/ER OC/APAP tablets may have less potential for abuse involving tampering compared with IR OC/APAP tablets.     

Recent progress in continuous and semi-continuous processing of solid oral dosage forms: a review

Context: Continuous processing is an innovative production concept well known and successfully used in other industries for many years. The modern pharmaceutical industry is facing the challenge of transition from a traditional manufacturing approach based on batch-wise production to a continuous manufacturing model.

Objective: The aim of this article is to present technological progress in manufacturing based on continuous and semi-continuous processing of the solid oral dosage forms.

Methods: Single unit processes possessing an alternative processing pathway to batch-wise technology or, with some modification, an altered approach that may run continuously, and are thus able to seamlessly switch to continuous manufacturing are briefly presented. Furthermore, the concept of semi-continuous processing is discussed. Subsequently, more sophisticated production systems created by coupling single unit processes and comprising all the steps of production, from powder to final dosage form, were reviewed. Finally, attempts of end-to-end production approach, meaning the linking of continuous synthesis of API from intermediates with the production of final dosage form, are described.

Results: There are a growing number of scientific articles showing an increasing interest in changing the approach to the production of pharmaceuticals in recent years. Numerous scientific publications are a source of information on the progress of knowledge and achievements of continuous processing. These works often deal with issues of how to modify or replace the unit processes in order to enable seamlessly switching them into continuous processing. A growing number of research papers concentrate on integrated continuous manufacturing lines in which the production concept of “from powder to tablet” is realized. Four main domains are under investigation: influence of process parameters on intermediates or final dosage forms properties, implementation of process analytical tools, control-managing system responsible for keeping continuous materials flow through the whole manufacturing process and the development of new computational methods to assess or simulate these new manufacturing techniques. The attempt to connect the primary and secondary production steps proves that development of continuously operating lines is possible.

Conclusion: A mind-set change is needed to be able to face, and fully assess, the advantages and disadvantages of switching from batch to continuous mode production.     

New nanomicelle curcumin formulation for ocular delivery: improved stability,solubility, and ocular anti-inflammatory treatment

Context: A stable topical ophthalmic curcumin formulation with high solubility, stability, and efficacy is needed for pharmaceutical use in clinics.

Objectives: The objective of this article was to describe a novel curcumin containing a nanomicelle formulation using a polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol (PVCL–PVA–PEG) graft copolymer.

Methods: Nanomicelle curcumin was formulated and optimized and then further evaluated for in vitro cytotoxicity/in vivo ocular irritation, in vitro cellular uptake/in vivo corneal permeation, and in vitro antioxidant activity/in vivo anti-inflammatory efficacy.

Results: The solubility, chemical stability, and antioxidant activity were greatly improved after the encapsulation of the PVCL–PVA–PEG nanomicelles. The nanomicelle curcumin ophthalmic solution was simple to prepare and the nanomicelles are stable to the storage conditions, and it had good cellular tolerance. Nanomicelle curcumin also had excellent ocular tolerance in rabbits. The use of nanomicelles significantly improved in vitro cellular uptake and in vivo corneal permeation as well as improved anti-inflammatory efficacy when compared with a free curcumin solution.

Conclusions: These findings indicate that nanomicelles could be promising topical delivery systems for the ocular administration of curcumin.     

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.