Supercritical Fluid Extraction with CO2 of Curcuma longa L. in Comparison to Conventional Solvent Extraction.

Curcuma longa L. is a traditional medicinal and spice plant containing a variety of lipophilic active substances with promising therapeutic properties. In this work, the solvent properties of supercritical carbon dioxide in a pressure and temperature range of 75-425 bar and 35-75 °C were investigated when Curcuma longa rhizomes were extracted. The three main curcuminoids, namely curcumin, demethoxycurcumin, and bisdemethoxycurcumin, together with the three main constituents of the essential oil, i.e., ar-turmerone, α-turmerone, and ß-turmerone, were analyzed in the resulting extracts. For statistical evaluation, experiments were performed employing a full factorial design, in which flow rate, extraction time, and drug load were kept constant. Within the given conditions, the experimental design revealed an optimum yield of all aforementioned substances, when supercritical carbon dioxide extraction was performed at 425 bar and 75 °C. For comparison, solvent extracts using methanol and n-hexane were prepared and their main components were characterized using LC-MS. The stability of the extracts was monitored upon storage for 6 months at 22 and 40 °C under protection from light. The decomposition of individual compounds was mainly observed in the presence of residual water in the extracts.

Supercritical Fluid Technology for the Development of 3D Printed Controlled Drug Release Dosage Forms.

Supercritical CO2 loading of preformed 3D printed drug carriers with active pharmaceutical ingredients (APIs) shows great potential in the development of oral dosage forms for future personalized medicine. We designed 3D printed scaffold like drug carriers with varying pore sizes made from polylactic acid (PLA) using a fused deposition modelling (FDM) 3D printer. The 3D printed drug carriers were then loaded with Ibuprofen as a model drug, employing the controlled particle deposition (CPD) process from supercritical CO2. Carriers with varying pore sizes (0.027-0.125 mm) were constructed and loaded with Ibuprofen to yield drug-loaded carriers with a total amount of 0.83-2.67 mg API (0.32-1.41% w/w). Dissolution studies of the carriers show a significantly decreasing dissolution rate with decreasing pore sizes with a mean dissolution time (MDT) of 8.7 min for the largest pore size and 128.2 min for the smallest pore size. The API dissolution mechanism from the carriers was determined to be Fickian diffusion from the non-soluble, non-swelling carriers. Using 3D printing in combination with the CPD process, we were able to develop dosage forms with individually tailored controlled drug release. The dissolution rate of our dosage forms can be easily adjusted to the individual needs by modifying the pore sizes of the 3D printed carriers.

An Insight Into the Impact of Polymers on the Hydrate Conversion of Olanzapine Form I in Aqueous Suspensions.

The potential of polyethyleneglycol (PEG), polyvinylpyrrolidone (PVP), and hydroxypropylcellulose (HPC) to inhibit the hydration of olanzapine (OLZ) in aqueous environments was assessed. OLZ Form I (OLZ) suspended in water (A) or in aqueous polymer solutions (2%, 0.2%, 0.02%, and 0.002%) (PEG 6000 [B], PEG 40,000 [C], HPC LF [D], or PVP K30 [E]). Filtered samples were analyzed by different techniques (X-ray powder diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, 1H-nuclear magnetic resonance spectroscopy). OLZ hydration showed to be faster in water than in PEG solutions, regardless of the polymer molecular weight. OLZ in D and E suspensions remained anhydrous at concentrations of 2%-0.02%. The NMR measurements revealed that all of these polymers were able to establish hydrogen bonds with the OLZ molecule and increased its saturation solubility, but only D and E showed to increase the wettability of the OLZ particles due to binding of these polymers to the surface of hydrate nuclei/first crystals OLZ crystals. This study provided an insight into the mechanisms of OLZ hydrate protection by polymers. It confirmed the advantage of using PVP K30 or HPC LF in wet granulation in concentrations as low as 0.02% to prevent formation of OLZ hydrates, due to the combined effect of H-bond ability and the strong bonding of these polymers to the surface of the crystals.

Effect of polymers in moisture sorption and physical stability of polymorphic olanzapine.

The study aims to elucidate the transformations of anhydrous olanzapine Form I (OLZ FI) into the hydrate forms, when stored at a high relative humidity or suspended in an aqueous media, in the presence of polymers. OLZ FI and physical mixtures (3:1 and 1:1, as powders or compacts) of olanzapine with polyethylene glycol (PEG-6000), polyvinylpyrrolidone (PVP K25) and hydroxypropylcellulose (HPC-LF) were stored (75%RH/25°C, 75%RH/40°C and 93%RH/25°C) for 28days. OLZ FI and the physical mixtures were also suspended in water under stirring (200rpm/60min). Samples were collected at different time points and vacuum filtered. OLZ FI showed to hydrate at 75%RH/25°C when stored in the presence of HPC and PEG. At 93%RH all polymers affected the kinetics of hydration of OLZ FI with PVP as the only polymer with the ability to minimize the formation of the hydrate. When olanzapine was suspended in water with HPC and PVP the formation of the hydrate was inhibited. Compaction of the powders before storage led to an increase of the hydrate conversion rate of olanzapine on the first week of storage, due to a partial amorphisation of olanzapine present at the tablet surface. When stored at high humidity environments OLZ FI converted into dihydrate D and, when exposed to aqueous environments in the presence of different polymers converted into dihydrates B and E. From an industrial point of view, this study highlighted the importance of the excipient's choice for OLZ formulations, so that a final OLZ medicine can have a consistent quality and performance throughout the entire medicine's shelf life.

Role of moisture on the physical stability of polymorphic olanzapine.

The focus of this study was the understanding of the hydrate transformations of anhydrous olanzapine Forms I and II (the most common polymorphs) upon exposure to different moisture conditions (11, 53, 75, 93% RH) and direct contact with water (e.g. aqueous slurry) and the impact of hydration on the aqueous dissolution rates of the polymorphs. The kinetics of reversible transformations (anhydrate-hydrate phases) and the identification of polymorphs were evaluated by differential scanning calorimetry, thermogravimetry, infrared (DRIFT) and X-ray powder diffraction. The results showed that anhydrous Forms I and II have undergone water vapor phase induced transformations at 93% and 75% RH, respectively. At 93% RH Forms I and II showed to hydrate into dihydrates D and B, respectively, the latter with a higher hydration rate. The conversion of Form I into the dihydrate D showed to affect the dissolution rate of olanzapine (f2<50). As slurries both forms showed to hydrate into a mixture of two different Forms - dihydrate B and higher hydrate. The study provided an understanding of the conversion pathways of the different forms when they were exposed to humid air or aqueous environments, resembling the transformations that might occur during processing, storage or during the persecution of dissolution tests to assess the quality of dosage forms delivering olanzapine.

Simultaneous formation and micronization of pharmaceutical cocrystals by rapid expansion of supercritical solutions (RESS).

PURPOSE: We investigated the RESS process as a means of simultaneous micronization and cocrystallization of a model drug with poor aqueous solubility. METHODS: 1:1 cocrystals of ibuprofen (IBU) and nicotinamide (NA) were produced with a pilot scale unit for RESS processing.IBU and NA were dissolved in scCO2 at 30 MPa and 50°C. After 24 h, the supercritical solution was expanded at a medium CO2 flow rate of 3.8 kg/h during 60 min into an expansion vessel kept at ambient conditions. Cocrystals were identified with DSC, XRD and confocal Raman microscopy (CRM) and further characterized by SEM, specific surface area, wetting ability, solubility and dissolution testing. RESULTS: Judging by DSC, XRD and CRM, cocrystals with high purity could be produced with the RESS technique. Micronization via RESS was successful, since the specific surface area of RESS cocrystals was increased almost tenfold in comparison to cocrystals produced by slow solvent evaporation. Due to the additional micronization, the mean dissolution time of IBU from RESS cocrystals was decreased. CONCLUSIONS: RESS cocrystallization offers the advantage of combining micronization and cocrystallization in a single production step. For drugs with dissolution-limited bioavailability, RESS cocrystallization may therefore be a superior approach in comparison to established cocrystallization techniques.

Delivery of drugs from laminar co-extrudates manufactured by a solvent-free process at room temperature.

This work aims to design and manufacture laminar co-extrudates as a new dosage form for the delivery of drugs. Co-extrudates made of lipid-based materials with a laminar shape were manufactured at room temperature in the absence of solvents and assessed over time for their mechanical properties (bending strength, deformation, stiffness, and elasticity), density, porosity, thermal behavior and main mechanism of drug release. The study has shown that the extrusion force at steady state increased with the extrusion rate and with the number of layers. The bending strength and stiffness of extrudates increased over time. Laminar co-extrudates with higher number of layers presented a decreasing dissolution efficiency of 38.3 ± 0.6%, 23.0 ± 0.2%, and 12.3 ± 0.2%, for mono-, bi-, and trilayer, respectively. After 90 days, the density, the deformation, and elasticity decreased: trilayer extrudates were the denser and the ones to present the lowest ability to deform and the highest elasticity, whereas monolayer extrudates were the less dense presenting the highest ability to deform. Changes were more evident in the first days after manufacture leading to stabilization over time. Laminar (co-)extrudates have been confirmed as an innovative dosage form for tailored delivery of drugs made without solvents at room temperature.

Multilayer laminar co-extrudate as a novel controlled release dosage form.

Design of a new dosage form manufactured by laminar extrusion for oral administration of drugs. Different mixtures of materials (microcrystalline cellulose [MCC], hydroxypropyl methylcellulose [HPMC], lactose [LAC], dicalcium phosphate [DCP], coumarin [COU], propranolol hydrochloride [PRO], water [W]) were prepared prior to laminar extrusion. Mono, bi and tri layer extrudates were manufactured and evaluated for extrudability, drying, water uptake and swelling ability and in vitro characterization of the drug release. Good quality extrudates were manufactured with higher HPMC molecular weight and fraction in formulation at an extrusion rate of 400 mm/min and slow drying (forced air stream), otherwise surface roughness, thickness in-homogeneity, bending and shark skin were present in the extrudates. Swelling of extrudates was dependent on HPMC fraction and molecular weight (60% up to 90% weight gain for low and high polymer chains, respectively) and the presence of either MCC or DCP. The release of drug was dependent on its solubility (PRO>COU), the fraction of HPMC (low>high fractions), the type of diluent (DCP>MCC) and number of layers (1>2>3 layers). By designing the number and type of layers, dosage forms with well-defined release-kinetics can be tailored. The study has shown the ability of the technology of extrusion to manufacture a controlled release dosage form in a continuous fashion.

Production of dosage forms for oral drug delivery by laminar extrusion of wet masses.

Laminar extrusion of wet masses was studied as a novel technology for the production of dosage forms for oral drug delivery. Extrusion was carried out with a ram extruder. Formulations contained either microcrystalline cellulose (MCC) or dicalcium phosphate (DCP) as diluent, hydroxypropyl methylcellulose (HPMC), lactose, and water. Extrudates were characterized for their tensile strength, Young's modulus of elasticity, water absorption, gel forming capacity, and release of two model drugs, coumarin (COU) and propranolol hydrochloride (PRO). Cohesive extrudates could be produced with both filling materials (MCC and DCP) when HPMC was included as a binder at low amounts (3.3-4.5% w/w dry weight). Employing more HPMC, the elasticity of the wet masses increased which resulted in distinct surface defects. For MCC, the maximum HPMC amount that could be included in the formulations (15% w/w dry weight) did not affect the mechanical properties or decrease the drug release significantly. For DCP extrudates, the maximally effective HPMC amount was 30% (w/w dry weight) with influence on both the mechanical properties and drug release. This study suggests that laminar extrusion of wet masses is a feasible technique for the production of dosage forms for oral drug delivery.

Drug loading into beta-cyclodextrin granules using a supercritical fluid process for improved drug dissolution.

To improve dissolution properties of drugs, a supercritical fluid (SCF) technique was used to load these drugs into a solid carrier. In this study, granules based on beta-cyclodextrin (betaCD) were applied as a carrier for poor water-soluble drug and loaded with a model drug (ibuprofen) using two different procedures: controlled particle deposition (CPD), SCF process and solution immersion (SI) as a conventional method for comparison. Using the CPD technique, 17.42+/-2.06wt.% (n=3) ibuprofen was loaded into betaCD-granules, in contrast to only 3.8+/-0.15wt.% (n=3) in the SI-product. The drug loading was confirmed as well by reduction of the BET surface area for the CPD-product (1.134+/-0.07m(2)/g) compared to the unloaded-granules (1.533+/-0.031m(2)/g). Such a reduction was not seen in the SI-product (1.407+/-0.048m(2)/g). The appearance of an endothermic melting peak at 77 degrees C and X-ray patterns representing ibuprofen in drug-loaded granules can be attributed to the amount of ibuprofen loaded in its crystalline form. A significant increase in drug dissolution was achieved by either drug-loading procedures compared to the unprocessed ibuprofen. In this study, the CPD technique, a supercritical fluid process avoiding the use of toxic or organic solvents was successfully applied to load drug into solid carriers, thereby improving the water-solubility of the drug.

Direct drug loading into preformed porous solid dosage units by the controlled particle deposition (CPD), a new concept for improved dissolution using SCF-technology.

The controlled particle deposition (CPD), a supercritical fluid precipitation process, is used to load porous tablets with ibuprofen to improve drug dissolution. Porous tablets (porosity 44.3 +/- 5.5%), consisting of microcrystalline cellulose pellets and hydroxyethylcellulose, or sugar cubes (porosity 37.2 +/- 0.5%), are used as carrier material. Loading experiments are conducted at 313 K and 25 MPa, drug concentrations between 6.25 and 33.3 mg ibuprofen/mL supercritical carbon dioxide and contact times of 15.5 h or 5 min. The resulting products have drug contents of 3-5 g ibuprofen/mL void volume in the carrier. Comparison of a predicted value, calculated from pore volume and loading concentration to the actual drug concentrations yielded by the loading process demonstrates the efficiency and controllability of the process. The mean particle size d(50) of deposited ibuprofen is around 25 microm, half the size of the starting material. Drug dissolution from loaded carriers is significantly increased by a rise in the dissolution coefficient from 0.07 min(-1) for the starting material to 0.13 or 0.14 min(-1) for the CPD products. The CPD method therefore is presented as a feasible and controllable process to load porous solid dosage forms with drug particles in order to improve dissolution.

Comparative evaluation of ibuprofen/beta-cyclodextrin complexes obtained by supercritical carbon dioxide and other conventional methods.

PURPOSE: The preparation of drug/cyclodextrin complexes is a suitable method to improve the dissolution of poor soluble drugs. The efficacy of the Controlled Particle Deposition (CPD) as a new developed method to prepare these complexes in a single stage process using supercritical carbon dioxide is therefore compared with other conventional methods. MATERIALS AND METHODS: Ibuprofen/beta-cyclodextrin complexes were prepared with different techniques and characterized using FTIR-ATR spectroscopy, powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). In addition, the influences of the processing technique on the drug content (HPLC) and the dissolution behavior were studied. RESULTS: Employing the CPD-process resulted in a drug content of 2.8+/-0.22 wt.% in the carrier. The material obtained by CPD showed an improved dissolution rate of ibuprofen at pH 5 compared with the pure drug and its physical mixture with beta-cyclodextrin. In addition CPD material displays the highest dissolution (93.5+/- 2.89% after 75 min) compared to material obtained by co-precipitation (61.3 +/-0.52%) or freeze-drying (90.6 +/-2.54%). CONCLUSION: This study presents the CPD-technique as a well suitable method to prepare a drug/beta-cyclodextrin complex with improved drug dissolution compared to the pure drug and materials obtained by other methods.

Quantitation of talinolol and other beta-blockers by capillary electrophoresis for in vitro drug absorption studies.

A capillary zone electrophoresis method is described for the enantioseparation of talinolol using heptakis(2,3-diacetyl-6-sulfo)-beta-cyclodextrin (HDAS-beta-CD) as a chiral selector. After liquid-liquid extraction of talinolol from physiological solution, electrokinetic injection was employed to improve the sensitivity. The use of a coated capillary was necessary to achieve stable and reproducible enantioseparations. A baseline separation of the talinolol enantiomers was achieved in less than 10 min using 100 mM phosphate solution as background electrolyte and pH 3.5, at the presence of 3.0 mM HDAS-beta-CD and at 20 degrees C. In addition, this analytical condition proved to be useful for the enantioseparation of a number of other beta-blocking agents such as alprenolol, atenolol, bisoprolol, celiprolol, metipranolol, oxprenolol, and sotalol. For determining talinolol, the method could be validated in terms of precision, accuracy and linearity, and was found to be suitable in determination of talinolol enantiomers in highly diluted samples obtained from in vitro experiments.

Quantitation of the enantiomers of ofloxacin by capillary electrophoresis in the parts per billion concentration range for in vitro drug absorption studies.

Ofloxacin, a chiral fluoroquinolone, possesses two optical isomers. The antibacterial activity of S-(-)-ofloxacin is reported to be 8-128 times higher than that of R-(+)-ofloxacin. A capillary zone electrophoresis method has been developed to quantify the enantiomers of ofloxacin in high diluted samples (20-700 ng/ml for each enantiomer). After fluid-fluid extraction of ofloxacin from physiological solution electrokinetic injection was employed to improve the sensitivity. The method was optimised using a central composite design. Four experimental factors were investigated: the background electrolyte concentration, the methyl-beta-cyclodextrin concentration, the buffer pH and the temperature. The amount migrated into the capillary, determined by the peak area, the resolution between the ofloxacin enantiomers, the migration time and the generated current were evaluated as responses. The quantification limit is 11.4 ng/ml for S-ofloxacin and 10.8 ng/ml for R-ofloxacin. The method has shown good validation data in terms of precision and recovery rate.