Automated Non-Sterile Pharmacy Compounding: A Multi-Site Study in European Hospital and Community Pharmacies with Pediatric Immediate Release Propranolol Hydrochloride Tablets.

Pharmacy compounding, the art and science of preparing customized medications to meet individual patient needs, is on the verge of transformation. Traditional methods of compounding often involve manual and time-consuming processes, presenting challenges in terms of consistency, dosage accuracy, quality control, contamination, and scalability. However, the emergence of cutting-edge technologies has paved a way for a new era for pharmacy compounding, promising to redefine the way medications are prepared and delivered as pharmacy-tailored personalized medicines. In this multi-site study, more than 30 hospitals and community pharmacies from eight countries in Europe utilized a novel automated dosing approach inspired by 3D printing for the compounding of non-sterile propranolol hydrochloride tablets. CuraBlend® excipient base, a GMP-manufactured excipient base (pharma-ink) intended for automated compounding applications, was used. A standardized study protocol to test the automated dosing of tablets with variable weights was performed in all participating pharmacies in four different iterative phases. Integrated quality control was performed with an in-process scale and NIR spectroscopy supported by HPLC content uniformity measurements. In total, 6088 propranolol tablets were produced at different locations during this study. It was shown that the dosing accuracy of the process increased from about 90% to 100% from Phase 1 to Phase 4 by making improvements to the formulation and the hardware solutions. The results indicate that through this automated and quality controlled compounding approach, extemporaneous pharmacy manufacturing can take a giant leap forward towards automation and digital manufacture of dosage forms in hospital pharmacies and compounding pharmacies.

Nanoformulation and Evaluation of Oral Berberine-Loaded Liposomes.

Berberine (BBR) is a poorly water-soluble quaternary isoquinoline alkaloid of plant origin with potential uses in the drug therapy of hypercholesterolemia. To tackle the limitations associated with the oral therapeutic use of BBR (such as a first-pass metabolism and poor absorption), BBR-loaded liposomes were fabricated by ethanol-injection and thin-film hydration methods. The size and size distribution, polydispersity index (PDI), solid-state properties, entrapment efficiency (EE) and in vitro drug release of liposomes were investigated. The BBR-loaded liposomes prepared by ethanol-injection and thin-film hydration methods presented an average liposome size ranging from 50 nm to 244 nm and from 111 nm to 449 nm, respectively. The PDI values for the liposomes were less than 0.3, suggesting a narrow size distribution. The EE of liposomes ranged from 56% to 92%. Poorly water-soluble BBR was found to accumulate in the bi-layered phospholipid membrane of the liposomes prepared by the thin-film hydration method. The BBR-loaded liposomes generated by both nanofabrication methods presented extended drug release behavior in vitro. In conclusion, both ethanol-injection and thin-film hydration nanofabrication methods are feasible for generating BBR-loaded oral liposomes with a uniform size, high EE and modified drug release behavior in vitro.

Quasi-Dynamic Dissolution of Electrospun Polymeric Nanofibers Loaded with Piroxicam.

We investigated and monitored in situ the wetting and dissolution properties of polymeric nanofibers and determined the solid-state of a drug during dissolution. Piroxicam (PRX) was used as a low-dose and poorly-soluble model drug, and hydroxypropyl methylcellulose (HPMC) and polydextrose (PD) were used as carrier polymers for electrospinning (ES). The initial-stage dissolution of the nanofibers was monitored in situ with three-dimensional white light microscopic interferometry (SWLI) and high-resolution optical microscopy. The physical solid-state characterization of nanofibers was performed with Raman spectroscopy, X-ray powder diffraction (XRPD), and scanning electron microscopy (SEM). We showed that PRX recrystallizes in a microcrystalline form immediately after wetting of nanofibers, which could lead to enhanced dissolution of drug. Initiation of crystal formation was detected by SWLI, indicating: (1) that PRX was partially released from the nanofibers, and (2) that the solid-state form of PRX changed from amorphous to crystalline. The amount, shape, and size of the PRX crystals depended on the carrier polymer used in the nanofibers and dissolution media (pH). In conclusion, the present nanofibers loaded with PRX exhibit a quasi-dynamic dissolution via recrystallization. SWLI enables a rapid, non-contacting, and non-destructive method for in situ monitoring the early-stage dissolution of nanofibers and regional mapping of crystalline changes (re-crystallization) during wetting. Such analysis is crucial because the wetting and dissolution of nanofibers can greatly influence the performance of nanofibrous drug delivery systems in pharmaceutical and biomedical applications.

Suberin Fatty Acids from Outer Birch Bark: Isolation and Physical Material Characterization.

The isolation and physical material properties of suberin fatty acids (SFAs) were investigated with special reference to their potential applications as novel pharmaceutical excipients. SFAs were isolated from outer birch bark (OBB) with a new extractive hydrolysis method. The present simplified isolation process resulted in a moderate batch yield and chemical purity of SFAs, but further development is needed for establishing batch-to-batch variation. Cryogenic milling was the method of choice for the particle size reduction of SFAs powder. The cryogenically milled SFAs powder exhibited a semicrystalline structure with apparent microcrystalline domains within an amorphous fatty acids matrix. The thermogravimetric analysis (TGA) of SFAs samples showed a good thermal stability up to 200 °C, followed by a progressive weight loss, reaching a plateau at about 95% volatilization at about 470 °C. The binary blends of SFAs and microcrystalline cellulose (MCC; Avicel PH 101) in a ratio of 25:75 (w/w) displayed good powder flow and tablet compression properties. The corresponding theophylline-containing tablets showed sustained or prolonged-release characteristics. The physicochemical and bulk powder properties of SFAs isolated from OBB are auspicious in terms of potential pharmaceutical excipient applications.

Development of Suberin Fatty Acids and Chloramphenicol-Loaded Antimicrobial Electrospun Nanofibrous Mats Intended for Wound Therapy.

Suberin fatty acids (SFAs) isolated from outer birch bark were investigated as an antimicrobial agent and biomaterial in nanofibrous mats intended for wound treatment. Electrospinning (ES) was used in preparing the composite nonwoven nanomats containing chloramphenicol (CAM; as a primary antimicrobial drug), SFAs, and polyvinylpyrrolidone (as a carrier polymer for ES). The X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, atomic force microscopy, and texture analysis were used for the physicochemical and mechanical characterization of the nanomats. ES produced nanofibrous mats with uniform structure and with an average fiber diameter ranging from 370 to 425 nm. Microcrystalline SFAs and crystalline CAM were found to undergo a solid-state transformation during ES processing. The ES process caused also the loss of CAM in the final nanofibers. In the texture analysis, the SFAs containing nanofibers exhibited significantly higher maximum detachment force to an isolated pig skin (p < 0.05) than that obtained with the reference nanofibers. CAM exists in an amorphous form in the nanofibers which needs to be taken into account in controlling the physical storage stability. In conclusion, homogeneous composite nanofibrous mats for wound healing can be electrospun from the ternary mixture(s) of CAM, SFAs, and polyvinylpyrrolidone.

Suberin fatty acids isolated from outer birch bark improve moisture barrier properties of cellulose ether films intended for tablet coatings.

We showed that the addition of suberin fatty acids (SFAs) even at small concentrations significantly improves the water vapor barrier properties of hydroxypropyl methylcellulose (HPMC) films. SFAs were isolated from the outer birch bark using extractive hydrolysis. The effects of SFAs on the film formation of aqueous HPMC were investigated with free films plasticized with polyethylene glycol (PEG 400). Special attention was paid on the physical solid-state, moisture barrier and mechanical stress-strain properties of films intended for tablet film coatings. Topography and surface morphology, glass transition temperature (Tg), tensile strength, Young's modulus, and water vapor permeation (WVP) of films were studied. The addition of SFAs lowered the Tg of films suggesting partial enhancement in film plasticization. The WVP of films decreased with increasing SFAs concentration up to 15% (calculated as a % w/w from a polymer weight). The WVP value for a non-suberized reference film and suberized film plasticized with PEG 400 was 2.13×10(-6) and 0.69[×10(-6) g/(mm(2)×h)×mm/Pa], respectively. The addition of SFAs impaired the mechanical stress-strain properties of HPMC films by reducing the deformation capacity of film. In conclusion, the film properties and performance of aqueous HPMC can be modified by including SFAs in the films.

Electrospun nanofibers as a potential controlled-release solid dispersion system for poorly water-soluble drugs.

Electrospinning was introduced as a novel technique for preparing controlled-release (CR) amorphous solid dispersions (SD) and polymeric nanofibers of a poorly water-soluble drug. Piroxicam (PRX) was used as a low-dose poorly-soluble drug and hydroxypropyl methylcellulose (HPMC) as an amorphous-state stabilising carrier polymer in nanofibers. Raman spectroscopy, X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) were used in the physical characterisation of the CR-SD nanofibers. Special attention was paid on the effects of a polymer and solvent system on the solid-state properties and physical stability of nanofibers. The average dry diameter of the electrospun CR-SD nanofibers ranged from 400 to 600 nm (SEM). PRX existed in amorphous form in the nanofibers immediately after fabrication and after a short-term (3-month) aging at low temperature (6-8 °C/0% RH) and ambient room temperature (22 °C/0% RH). At higher temperature and humidity (30 °C/85% RH), however, amorphous PRX in the nanofibers tended to slowly recrystallise to PRX form III. The electrospun CR-SD nanofibers exhibited a short lag-time, the absence of initial burst release and zero-order linear CR dissolution kinetics. In conclusion, electrospinning can be used to fabricate supersaturating CR-SD nanofibers of PRX and HPMC, and to stabilise the amorphous state of PRX.

Soluplus graft copolymer: potential novel carrier polymer in electrospinning of nanofibrous drug delivery systems for wound therapy.

Electrospinning is an effective method in preparing polymeric nanofibrous drug delivery systems (DDSs) for topical wound healing and skin burn therapy applications. The aim of the present study was to investigate a new synthetic graft copolymer (Soluplus) as a hydrophilic carrier polymer in electrospinning of nanofibrous DDSs. Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) was applied in the nonwoven nanomats loaded with piroxicam (PRX) as a poorly water-soluble drug. Raman spectroscopy, X-ray powder diffraction, differential scanning calorimetry, and scanning electron microscopy (SEM) were used in the physical characterization of nanofibrous DDSs. According to the SEM results, the drug-loaded PCL-PVAc-PEG nanofibers were circular in cross-section with an average diameter ranging from 500 nm up to 2 µm. Electrospinning stabilized the amorphous state of PRX. In addition, consistent and sustained-release profile was achieved with the present nanofibrous DDSs at the physiologically relevant temperature and pH applicable in wound healing therapy. In conclusion, electrospinning can be used to prepare nanofibrous DDSs of PCL-PVAc-PEG graft copolymer (Soluplus) and to stabilize the amorphous state of a poorly water-soluble PRX. The use of this synthetic graft copolymer can open new options to formulate nanofibrous DDSs for wound healing.

Nanometer depth resolution in 3D topographic analysis of drug-loaded nanofibrous mats without sample preparation.

We showed that scanning white light interferometry (SWLI) can provide nanometer depth resolution in 3D topographic analysis of electrospun drug-loaded nanofibrous mats without sample preparation. The method permits rapidly investigating geometric properties (e.g. fiber diameter, orientation and morphology) and surface topography of drug-loaded nanofibers and nanomats. Electrospun nanofibers of a model drug, piroxicam (PRX), and hydroxypropyl methylcellulose (HPMC) were imaged. Scanning electron microscopy (SEM) served as a reference method. SWLI 3D images featuring 29 nm by 29 nm active pixel size were obtained of a 55 µm × 40 µm area. The thickness of the drug-loaded non-woven nanomats was uniform, ranging from 2.0 µm to 3.0 µm (SWLI), and independent of the ratio between HPMC and PRX. The average diameters (n=100, SEM) for drug-loaded nanofibers were 387 ± 125 nm (HPMC and PRX 1:1), 407 ± 144 nm (HPMC and PRX 1:2), and 290 ± 100 nm (HPMC and PRX 1:4). We found advantages and limitations in both techniques. SWLI permits rapid non-contacting and non-destructive characterization of layer orientation, layer thickness, porosity, and surface morphology of electrospun drug-loaded nanofibers and nanomats. Such analysis is important because the surface topography affects the performance of nanomats in pharmaceutical and biomedical applications.

Solid-state properties of softwood lignin and cellulose isolated by a new acid precipitation method.

Solid-state and powder properties of softwood lignin and cellulose prepared by a new catalytic oxidation and acid precipitation method were characterized and compared with the commercial softwood and hardwood lignin and cellulose products. Catalytic pre-treated softwood lignin (CPSL) and cellulose (CPSC) were isolated from pine wood (Pinus sylvestris). CPSL with nearly micronized-scale particle size showed excellent powder flow and densification behavior due to the round shape and electrically minimum charged surface characteristics of particles. CPSL and the reference lignin studied were amorphous solids while CPSC exhibited a typical crystal lattice for cellulose I. In conclusion, physicochemical material properties of lignin and cellulose can be modified for biomedical and pharmaceutical applications with the present catalytic oxidation and acid precipitation method.

Insight into the solubility and dissolution behavior of piroxicam anhydrate and monohydrate forms.

The aim of the present study was two-fold: (1) to investigate the effect of pH and presence of surfactant sodium lauryl sulphate (SLS) on the solubility and dissolution rate of two solid-state forms of piroxicam (PRX), anhydrate (PRXAH) and monohydrate (PRXMH), and (2) to quantitatively assess the solid-phase transformation of PRXAH to PRXMH in slurry with a special interest to the impact on the solubility and dissolution behavior of the drug. X-ray powder diffractometry (XRPD), Raman spectroscopy and scanning electron microscopy (SEM) were used for characterization of the solid-state forms. Phase transformation was monitored in slurry by means of in-line Raman spectroscopy, and the partial least squares (PLS) regression model was used for predicting the amount of PRXMH. The results showed that the solubility and dissolution rate of PRXAH were higher compared to PRXMH at different pHs. The pH and presence of SLS together affected the solubility and dissolution rate of different PRX forms. The lowest solubility values and dissolution rates for PRX forms were observed in distilled water (pH 5.6) at 37 °C. The changes in the dissolution rate could be explained by the hydrate formation during solubility testing. The rate of hydrate formation was also dependent on the pH of the dissolution medium.

Phytochemical analysis of the essential oil of Thymus serpyllum L. growing wild in Estonia.

Variations in the essential oil composition of Thymus serpyllum L., growing wild in Estonia (33 samples) and in some other countries (Russia, Latvia and Armenia, seven samples) were determined. The oil were obtained from Estonia (46 samples) in yields 0.6-4.4 and 1.9-8.2 mL kg(-1) in other countries. The T. serpyllum herb grown in Estonia usually did not confirmed to the EP standard in the aspect of the essential oil contents (3.0 mL kg(-1)). Variations in the essential oil composition of wild thyme were studied using capillary gas chromatographic methods. A total of 94 components were identified. Thymol and carvacrol, mentioned in literature as principial components, are not the main components of the essential oil of wild thyme growing in Estonia. (E)-nerolidol, caryophyllene oxide, myrcene and borneol chemotypes of wild thyme drug are distinguishable. The chemical composition of samples from Russia, Latvia and Armenia is very variable.

Content and composition of the essential oil of Thymus serpyllum L. growing wild in Estonia.

OBJECTIVE: The aim of this work was to analyze the essential oil content and its composition in the drug (Serpylli herba) of wild thyme (Thymus serpyllum L.) originating from 20 different natural places of growth in Estonia. MATERIAL AND METHODS: The quantitative content of essential oil was determined according to the method of European Pharmacopoeia. Gas chromatographic analysis of essential oils was carried out using a gas chromatography with flame ionization detector on two fused silica capillary columns with bonded stationary phases NB-30 and SW-10. The identification of the oil components was accomplished by comparing their retention indices on two columns with the retention indices values of standard compounds, with our retention indices data bank and with literature data. The results obtained were confirmed by gas chromatography / mass spectrometry. RESULTS: The content of essential oil is between 0.6 and 4 ml/kg and usually is not in conformity with European Pharmacopoeia standard (3 ml/kg). There were 55 components identified in the essential oil of wild thyme of Estonian origin. Differently from the data in the literature of foreign countries, thymol and carvacrol are not the main components of the essential oil of wild thyme growing in Estonia. The main components here are (E)-nerolidol, caryophyllene oxide, myrcene, (E)-beta-caryophyllene and germacrene D. CONCLUSION: In Estonia, the (E)-nerolidol-caryophyllene oxide, (E)-nerolidol-myrcene and myrcene chemotypes of wild thyme drug are distinguishable.