Aqueous Solutions Of Mannitol Research Articles

Development of a Nondestructive Monitoring Technique for Vial Freeze-Drying Process using Microwave Resonance Spectroscopy

In this study, we developed a nondestructive monitoring technique for the drying progress of products in vials during the freeze-drying process using microwave resonance spectroscopy. An aqueous mannitol solution, commonly used as an excipient for injectable drugs, was used as the model material. The drying progress was determined using a mathematical model (i.e., Rp−Kv model), in which the parameters of mass and heat transfer were experimentally determined while considering the variation of the drying progress and position of the product on the drying shelf. A strong correlation was found between the extent of drying and changes in the microwave resonance spectrum. The simulation results were regressed against the changes in the resonance peak frequency and resonance intensity. Using this regression equation, the extent of drying could be predicted from the acquired spectral data. In this way, we were able to estimate the design space (the relationship between the operating conditions, internal temperature of the product, and sublimation rate), which changed with the extent of drying from the spectrum obtained inline, showing that it is possible to set the appropriate operating conditions based on the spectra.

Novel Unsteady State Method of Measuring Permeability Tested on Fabric Materials

The necessity of measuring permeability is encountered in number of applications and some of them have adequate measurement techniques available. However, in the fields of freeze drying, composite scaffolds, 3D printed materials, etc., the sample materials have unique shapes and sizes, which disables the use of standardized equipment. Hence, a novel method was developed to determine the permeability of a sample material by analyzing a high frequency unsteady state pressure measurement acquired during the permeation of a working fluid. The method is also suitable for in-line measurements due to the rapid acquisition and analysis. The developed method is novel, hence a comparison of the acquired results and the permeabilities measured with a standard device designed for measuring air permeability of fabric materials was made. Air was the permeating fluid in the novel unsteady state as well as in the referential steady state measurements. The measured permeabilities ranged from approximately 8 Da to 50 Da for the analyzed five fabric materials. The comparative analysis yielded an encouraging linear fit with a R2 = 0.98 by including only one unsteady state measurement of each fabric sample. In addition, the presented method was capable of detecting the difference in permeability of the freeze-dried 5 wt% and 12 wt% aqueous mannitol solutions, which exhibit different permeabilities due to the different porosities after the same process of lyophilization. The possibility of determining permeabilities of freeze-dried pharmaceuticals is essential for lyophilization process optimization.

Experimental and stochastic analysis of lyophilisation

The development of the freeze-drying processes through the use of a combination of targeted experiments and the application of multidimensional computational models is applied increasingly in pharmaceutical practice, especially for scale-up purposes. This study deals with the analysis of uncertainties in the data on material properties and model parameters, and their influence on the results delivered by advanced computational models of lyophilisation. As a means of uncertainty analysis, the Stochastic Collocation Method is applied, allowing the use of existing reliable deterministic models as black boxes in the stochastic computations. As a deterministic model, the lyophilisation model is used, based on the axisymmetric approximation of a vial, and the Boundary Element Method as a solver. Five parameters, covering material properties, process conditions and model constants, are selected for the sensitivity analysis simulation of the lyophilisation of an aqueous mannitol solution. The results show that during the initial stage of the primary drying heat transfer from the shelf is crucial, and that the uncertainties in the contact surface area and material properties of the vial play a more important role than the thermal properties of the drying material. When the temperature of the material reaches its distinct primary drying stage level the mass transfer through the porous cake becomes the most important, with great sensitivity to the Knudsen diffusivity in the porous cake. We observed uncertainties in the results for the primary drying time in the order of ±6%, and uncertainties in the results for temperatures of ±0.6°C in the frozen material and ±3°C in the porous cake. The uncertainty analysis proved to be a great help in determining the critical parameters in the heat and mass transfer during the important primary drying step, which led to a better definition of the numerical model for use in the context of design space determination.

Monitoring of the freezing stage in a freeze-drying process using IR thermography

This paper presents a new Process Analytical Technology based on the use of an infrared camera and a mathematical model to estimate the ice crystal size distribution obtained at the end of the freezing stage of a vial freeze-drying process. Both empirical laws and first-principle based equations, already presented in the Literature, may be used to this purpose, if the temperature gradient in the frozen product and the freezing front rate are obtained from the analysis of the thermal images. The resistance of the dried product to vapor flux may be then calculated from the distribution of the ice crystal diameters, thus enabling the use of a one-dimensional model for process simulation and optimization. Freeze-drying of 5% and 10% w/w aqueous sucrose solutions, and of 5% w/w aqueous mannitol solutions, were considered as case study. The results were validated comparing the calculated diameters of the pores of the dried cake, corresponding to the ice crystal diameters, with the results experimentally obtained from the analysis of the SEM images, and comparing the values of drying duration and maximum product temperature calculated with the mathematical model with those measured experimentally. Results evidences the effectiveness of the proposed system for process monitoring.

Formulating Inhalable Dry Powders Using Two-Fluid and Three-Fluid Nozzle Spray Drying

The spray drying process is widely applied for pharmaceutical particle engineering. The purpose of this study was to investigate advantages and disadvantages of two-fluid nozzle and three-fluid nozzle spray drying processes to formulate inhalable dry powders. Budesonide nanocomposite microparticles (BNMs) were prepared by co-spray drying of budesonide nanocrystals suspended in an aqueous mannitol solution by using a two-fluid nozzle spray dryingprocess. Budesonide-mannitol microparticles (BMMs) were prepared by concomitant spray drying of a budesonide solution and an aqueous mannitol solution using a spray drier equipped with a three-fluid nozzle. The resulting dry powders were characterized by using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA) and Raman microscopy. A Next Generation Impactor was used to evaluate the aerodynamic performance of the dry powders. XRPD and DMA results showed that budesonide remained crystalline in the BNMs, whereas budesonide was amorphous in the BMMs. Spray drying of mannitol into microparticles resulted in a crystalline transformation of mannitol, evident from XRPD, DSC and Raman spectroscopy analyses. Both BMMs and BNMs displayed a faster dissolution rate than bulk budesonide. The yield of BNMs was higher than that of BMMs. The mass ratio between budesonide and mannitol was preserved in the BNMs, whereas the mass ratio in the BMMs was higher than the theoretical ratio. Spray drying is an enabling technique for preparation of budesonide amorphous solid dispersions and nanocrystal-embedded microparticles. Two-fluid nozzle spray drying is superior to three-fluid nozzle spray drying in terms of yield.

Molecular interaction studies of antibiotic drug Doxycycline Hyclate with aqueous mannitol using volumetric and acoustic methods

The behaviour of Doxycycline Hyclate (DH) in aqueous mannitol solution was studied to explore molecular interactions at different temperatures. The volumetric and acoustic studies were used for investigating the interactions of drug Doxycycline Hyclate in water and aqueous mannitol system. The Density (ρ) and ultrasonic velocity (u) of Doxycycline Hyclate in water and in (0.1, 0.2 and 0.4) mol·kg− 1 aqueous solutions of mannitol have been measured at (305.15, 310.15 and 315.15 K) temperatures and atmospheric pressure. The density data was analysed with the help of Masson's equation. The positive value of (Φv0) for DH indicates solute-solvent interactions The solute-solute interactions were determined from Masson's coefficient, (Sv) in water-mannitol system at different temperatures. The ultrasonic velocity data of DH in water and water-mannitol system were used to determine adiabatic compressibility (β), intermolecular free length (Lf), and specific acoustic impedance (Z). The structure making/breaking behaviour of DH in water and water mannitol system is determined on the basis of Hepler's equation. The UV spectra for DH in water and water-mannitol system stand in support of molecular interactions between drug and mannitol.

Effect of polymers for aerolization properties of mannitol-based microcomposites containing meloxicam

The aim of this study was to develop respirable microcomposites of meloxicam and adjuvants (different polymers and amino acid) for inhalation as drug delivery systems for local lung therapy. Meloxicam was transformed into microcomposites, i.e. crystals of drug embedded in mannitol and other adjuvants. We focused on the influence of polymers concentration on the physico-chemical properties of the microparticles. The objective was to optimize the aerodynamic parameters of the particles and to achieve the fast release of meloxicam.The size of the meloxicam particles suspended in aqueous mannitol solution containing different additives was reduced by high-pressure homogenization. Dry powders were produced from the microsuspensions by a co-spray-drying technique. Morphological, structural and in vitro dissolution studies were presented. The in vitro aerosol performance was tested by using the multistage Next Generation Impactor.It was found that polyvinyl alcohol and polyvinylpyrrolidone, promoted the presence of individual microcomposites by decreasing the aggregation tendency. L-leucine improved the fine particle fraction content of the samples. The co-spray-dried mannitol-based formulations containing the additives released 90% of the meloxicam by dissolution in 5min. Aerodynamic assessment showed the fine particle fraction was >53% and the mass median aerodynamic diameter was <3.52μm. This study indicated that meloxicam microcomposites prepared according to the described procedure are suitable for pulmonary local anti-inflammatory and antifibrotic therapy.

The morphology of spray dried mannitol particles — The vital importance of droplet size

Abstract As the morphology of spray dried aqueous mannitol solutions is strongly influenced by the scale of the used spray dryer or more correctly by the droplet size generated in the spray dryer the purpose of this work is to carefully study and compare the morphologies and underlying particle formation mechanisms on lab and pilot scale. Therefore drying experiments of 15% [w/w] aqueous mannitol solutions were performed on a lab and pilot scale spray dryer at different outlet temperatures. The obtained spray dried products are intended to be used as carrier particles for pulmonary drug delivery. In order to show that the morphology is highly dependent on the initial droplet size, irrespective of the size of the used spray dryer, droplets of different size were dried in the pilot scale spray dryer at different air outlet temperatures. Additionally the influence of feed temperature on particle morphology was studied. For small droplets crystallization from a highly viscous liquid or even water-free melt is observed, leading to rough particles at high outlet temperatures and smooth particles at low temperatures. When drying larger droplets, however crystallization obviously starts from a more diluted solution leading to rougher surfaces, containing larger single crystals at lower outlet temperatures than at higher ones. For large droplets an increase in the mannitol solution feed temperature leads to particles of comparably rougher surface. No influence of feed temperature was observed for smaller droplets.

Improved Intestinal Absorption of a Poorly Water-Soluble Oral Drug Using Mannitol Microparticles Containing A Nanosolid Drug Dispersion

A nozzle for a spray dryer that can prepare microparticles of water-soluble carriers containing various nanoparticles in a single step was previously developed in our laboratory. To enhance the solubility and intestinal absorption of poorly water-soluble drugs, we used probucol (PBL) as a poorly water-soluble drug, mannitol (MAN) as a water-soluble carrier for the microparticles, and EUDRAGIT (EUD) as a polymer vehicle for the solid dispersion. PBL-EUD-acetone-methanol and aqueous MAN solutions were simultaneously supplied through different liquid passages of the spray nozzle and dried together. PBL-EUD solid dispersion was nanoprecipitated in the MAN solution using an antisolvent mechanism and rapidly dried by surrounding it with MAN. PBL in the dispersion vehicle was amorphous and had higher physical stability according to powder X-ray diffraction and differential scanning calorimetry analysis. The bioavailability of PBL in PBL-EUD S-100-MAN microparticles after oral administration in rats was markedly higher (14- and 6.2-fold, respectively) than that of the original PBL powder and PBL-MAN microparticles. These results demonstrate that the composite microparticles containing a nanosized solid dispersion of a poorly water-soluble drug prepared using the spray nozzle developed by us should be useful to increase the solubility and bioavailability of drugs after oral administration.

Spray dried mannitol carrier particles with tailored surface properties – The influence of carrier surface roughness and shape

The aim of this work was to study the performance of mannitol carrier particles of tailored surface roughness in dry powder inhaler formulations. Carrier particles of different surface roughness were prepared by spray drying of aqueous mannitol solutions at different outlet temperatures at a pilot-scale spray dryer. However, the carrier particles did not only change in surface roughness but also in shape. This is why the impact of carrier shape on the performance of carrier based dry powder inhalates was evaluated also. The highest fine particle fraction (FPF), that is the amount of active pharmaceutical substance, delivered to the deep lung, is achieved when using rough, spherical carrier particles (FPF=29.23±4.73%, mean arithmetic average surface roughness (mean Ra)=140.33±27.75nm, aspect ratio=0.925). A decrease of surface roughness (mean Ra=88.73±22.25nm) leads to lower FPFs (FPF=14.62±1.18%, aspect ratio=0.918). The FPF further decreases when irregular shaped particles are used. For those particles, the micronized active accumulates within the cavities of the carrier surface during the preparation of the powder mixtures. Upon inhalation, the cavities may protect the active from being detached from the carrier.

Effects of Process Variables on the Properties of Spray-Dried Mannitol and Mannitol/Disodium Cromoglycate Powders Suitable for Drug Delivery by Inhalation

Understanding the influence of process conditions on the properties of pharmaceutical products is critical to their optimal and cost-effective design and manufacture. The aim of this study was to investigate the effect of changing processing variables on the physical properties of spray-dried mannitol and co-spray-dried mannitol/disodium cromoglycate (DSCG) formulations intended for therapeutic inhalation. A 24 full factorial design was performed to assess the consequences of altering the following spray-drying parameters: feed flow rate, nozzle gas flow rate, drying gas inlet temperature, and aspirator capacity (drying gas flow rate). Aqueous solutions of mannitol and mannitol/DSCG were spray-dried using a laboratory-scale spray dryer, and the products were characterized in terms of particle size distribution, powder yield, and particle morphology. These physical properties were found to be affected mainly by two processing variables: nozzle gas flow rate and drying gas inlet temperature. In addition, optimal conditions for the production of inhalable mannitol powders were obtained, generating a yield of 90% by weight of round and smooth particles with a volume median diameter of 4.28 μm. Mannitol/DSCG formulations co-spray-dried in the same conditions had similar characteristics. The results of this study can be applied to controlled formulation of various spray-dried powders for inhalation.

Comparison between DSC and TMDSC in the investigation into frozen aqueous cryoprotectants solutions

Purpose: The influence of thermal parameters in the observation of thermal events and in the calculation of heat transformation in aqueous cryoprotectant solutions after freezing was investigated using conventional differential scanning calorimetry (DSC) and temperature-modulated DSC (TMDSC), respectively. Methods: The systems under study were formed by pure water and diluted aqueous solutions of mannitol, trehalose, sucrose, sorbitol, and glycine. The influence of different combinations of frequency and amplitude was analyzed in heating–cooling and heating-iso TMDSC scans. Results: Trehalose, sucrose, and sorbitol present a lesser critical temperature of primary drying than other cryoprotectants studied. The calorimetric variables selection is crucial to detect or not the thermal events, or to detect so with different numerical values. Then, the values of the calorimetric parameters determined are different if measured in a mode of heating–cooling or heating-iso. The TMDSC method-1 used in this study employs a higher number of cycles in each thermal event. The use of Lissajous figures and the study of the Cp in-phase signal evolution will allow us to understand the complexity of the events detected. Conclusions: The comparative study of both techniques points to the selection of conventional or modulated technique depending on the type of system and the nature of the studied events.

Application of a Four-fluid Nozzle Spray Drier to Prepare Inhalable Rifampicin-containing Mannitol Microparticles

The purpose of this study was to use a four-fluid nozzle spray drier as a new one-step method for preparing rifampicin (RFP)-containing mannitol microparticles. A RFP-acetone/methanol (2:1) solution and aqueous solutions of mannitol (MAN) were simultaneously supplied through different liquid passages of a four-fluid nozzle spray drier and then dried to obtain MAN microparticles containing RFP. Using a cascade impactor, the in vitro aerosol performance of RFP powder and RFP-MAN microparticles with 1:5, 1:10, and 1:20 ratios was compared. The in vivo retention of RFP in the lungs of rats after intratracheal administration of 1:20 RFP-MAN microparticles was also compared. The RFP-MAN microparticles had better aerosol performance than RFP powder and delivery to the lung stages improved as the fraction of MAN was increased. For the 1:20 RFP-MAN microparticles, deposition in stages 2-7 was approximately 43%, which is sufficient for treatment. Approximately 8% of the RFP-MAN microparticles were deposited in stages 6-7, which corresponds to alveoli containing alveolar macrophages. The initial retention of RFP in the lung following pulmonary delivery of 1:20 RFP-MAN microparticles was higher than following oral or intravenous administration of RFP, but the elimination was rapid, resulting in the disappearance of RFP from the lung within 4 h. The plasma concentration-time profile of RFP after intratracheal administration of 1:20 RFP-MAN microparticles was consistent with the profile for RFP retention in the lung. Addition of cholesterol or phosphatidylcholine to RFP had little effect on its retention in the lung. The RFP-MAN microparticles were effective for delivery of RFP to the lung, but the RFP rapidly removed from the lung into the blood circulation. This study demonstrated that RFP-containing MAN microparticles prepared in one step using the four-fluid nozzle spray drier efficiently deliver RFP to the lung, although methods must be developed to prolong its retention and improve targeting to alveolar macrophages.

Molar volume, viscosity and conductance studies of nickel sulphate in water and aqueous mannitol

Molar volume, viscosity and conductance of nickel sulphate in water and 2, 4 and 6 wt. % of aqueous mannitol solutions have been evaluated from density, viscosity and conductance data respectively at temperatures 303.15, 308.15, 313.15 and 318.15 K. The solute-solvent interactions for nickel sulphate in water and various compositions of aqueous mannitol have been inferred from Φ 0 v , B-coefficient of Jones-Dole equation and Λ 0 m values. The structure making/breaking behaviour of nickel sulphate is inferred from the sign of [∂ 2 Φ o v /∂T 2 ] p , dBldT and temperature coefficient of Walden product i.e. d(Λ 0 m η 0 )/dT values. It has been found that nickel sulphate behaves as structure-breaker in water and structure-maker in 2, 4 and 6 wt. % of aqueous mannitol solutions from molar volume, viscosity and conductance studies. The energy of activation for nickel sulphate in different composition of aqueous mannitol have also been calculated from conductance and viscosity data.

Investigation into the subambient behavior of aqueous mannitol solutions using temperature-controlled Raman microscopy

The aim was twofold; to demonstrate the ability of temperature-controlled Raman microscopy (TRM) to locate mannitol within a frozen system and determine its form; to investigate the annealing behavior of mannitol solutions at −30 °C. The different polymorphic forms of anhydrous mannitol as well as the hemihydrate and amorphous form were prepared and characterized using crystal or powder X-ray diffractometry (XRD) as appropriate and Raman microscopy. Mannitol solutions (3% w/v) were cooled before annealing at −30 °C. TRM was used to map the frozen systems during annealing and was able to differentiate between the different forms of mannitol and revealed the location of both β and δ polymorphic forms within the structure of the frozen material for the first time. TRM also confirmed that the crystalline mannitol is preferentially deposited at the edge of the frozen drop, forming a rim that thickens upon annealing. While there is no preference for one form initially, the study has revealed that the mannitol preferentially transforms to the β form with time. TRM has enabled observation of spatially resolved behavior of mannitol during the annealing process for the first time. The technique has clear potential for studying other crystallization processes, with particular advantage for frozen systems.

Glucose and Mannitol Diffusion in Human Dura Mater

An in vitro experimental study of the control of the human dura mater optical properties at administration of aqueous solutions of glucose and mannitol has been presented. The significant increase of the dura mater optical transmittance under action of immersion liquids has been demonstrated. Diffusion coefficients of glucose and mannitol in the human dura mater tissue at 20°C have been estimated as (1.63 ± 0.29) × 10 −6cm 2/s and as (1.31 ± 0.41) × 10 −6 cm 2/s, respectively. Experiments show that administration of immersion liquids allows for the effective control of tissue optical characteristics that make dura mater more transparent, thereby increasing the ability of light penetration through the tissue.

Effect of Osmolyte on the Micellization of SDS at Different Temperatures

was prepared (0.1, 0.2, 0.3, 0.6, and 0.8 M) and added slowly to the aqueous mannitol solutions (0.1, 0.2, 0.3, 0.6, and 0.8 M, respectively) placed in the thermostat. The specific conductance of the solution was recorded. The abrupt change in the initial slope value at a particular concentration was considered to be the cmc. Fluorescence spectra were recorded on a Hitachi model 65040 fluorimeter. The aggregation number of SDS in mannitol solutions was determined by the fluorescence quenching method 6

An Investigation Into the Subambient Behavior of Aqueous Mannitol Solutions Using Differential Scanning Calorimetry, Cold Stage Microscopy, and X-Ray Diffractometry

The subambient behavior of aqueous mannitol solutions is of considerable relevance to the preparation of freeze dried formulations. In this investigation the properties of 3% w/v mannitol solutions were investigated using differential scanning calorimetry (DSC), cold stage microscopy (CSM), and X-ray diffraction (XRD) to identify the thermal transitions and structural transformations undergone by this system. It was found that on cooling from ambient the system formed ice at circa −20°C while a further exotherm was seen at approximately −30°C. Upon reheating an endotherm was seen at circa −30°C followed immediately by an exotherm at circa −25°C. Temperature cycling indicated that the thermal transitions observed upon reheating were not reversible. Modulated temperature DSC (MTDSC) indicated that the transitions observed upon reheating corresponded to a glass transition immediately followed by recrystallization, XRD data showed that recrystallization was into the β form. Annealing at −35°C for 40min prior to cooling and reheating resulted in a maximum enthalpy being observed for the reheating exotherm. It is concluded that on cooling 3% w/v aqueous mannitol solutions an amorphous phase is formed that subsequently recrystallises into the β form. The study has also shown that DSC, CSM, and XRD are useful complementary techniques for the study of frozen systems. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association.

Wound-induced increases in phenolic content of fresh-cut lettuce is reduced by a short immersion in aqueous hypertonic solutions

Wounding during the preparation of fresh-cut lettuce induces the synthesis of phenylalanine ammonia lyase (PAL, EC 4.3.1.5), and the synthesis and accumulation of specific phenolic compounds (e.g., chlorogenic acid) that contribute to subsequent tissue browning. Increased PAL activity and phenolic content were not induced in non-wounded lettuce that was kept in close proximity to wounded tissue through either a vapor or aqueous signal. The phenolic content of fresh-cut Iceberg and Romaine lettuce was reduced in tissue pieces immediately immersed for 2 h in hypertonic aqueous mannitol solutions (0.3–0.9 M) after cutting. Re-wounding tissue segments 1 day after the initial excision did not produce a second rise in PAL activity in those pieces in which wound-induced increases in PAL activity had been suppressed by a previous soak in hypertonic aqueous mannitol solutions. It appears that the hypertonic solution did not cause the loss of a portion of the wound signal through efflux of water from the tissue, but rather induced a general stress-related resistance to further abiotic stresses.

Freeze‐drying using vacuum‐induced surface freezing

A method of freezing during freeze‐drying, which avoids undercooling of a solution and allows growth of large, dendritic ice crystals, was investigated. Aqueous solutions of mannitol, sucrose, or glycine were placed under a chamber vacuum of approximately 1 mbar at a shelf temperature of + 10°C. Under these conditions, the solutions exhibit surface freezing to form an ice layer of approximately 1–3 mm thickness. On releasing the vacuum and lowering the shelf temperature to below the freezing point of the ice in the solution, crystal growth occurs to yield large, chimney‐like ice crystals. The duration of primary drying of a frozen cake—as measured by using inverse comparative pressure measurement—was up to 20% shorter than when using a “moderate” freezing procedure (2 K shelf temperature per min). With mannitol, however, the residual moisture content of the final dried product was higher than with moderate freezing, and with sucrose and glycine there was no difference. These findings are related to the structures of the dried cakes formed during freezing, as examined by light microscopy and wide‐angle X‐ray diffraction. The introduction of an annealing step (4 h at a shelf temperature slightly above the onset melting point of the ice in the frozen cake) combined with the vacuum‐induced surface freezing procedure maintains the rapid primary drying and produces a low residual moisture (0.2%) for the freeze‐dried mannitol solution.