Biomedical subjects

Jukka Rantanen

Publications and source records attributed to Jukka Rantanen.

At least 19 recordsLinked to original sources

PubMed2006

Crystallization of glycine with ultrasound.

Sonocrystallization has proved to be an efficient tool to influence the external appearance and structure of a crystalline product obtained by various crystallization methods. The present work focuses on high intensity sonocrystallization of glycine by varying amplitude of ultrasound with an ultrasound frequency of 20kHz at two temperature ranges 40-50 and 20-30 degrees C in a jacketed 250-ml cooling crystallizer equipped with a stirrer. The polymorph composition of the obtained crystals was analyzed with a temperature variable X-ray powder diffractometer (XRPD). XRPD results showed that, besides the operating temperature, the glycine polymorphism was affected also by insonation. This was especially the case at the lower temperature range. Furthermore, based on the heat balance within the crystallizer, an increase in required cooling capacity was presented as a function of increasing ultrasound power. This study also showed, the higher the ultrasound amplitude the smaller the crystals obtained.

Chemistry, Pharmaceutical↗

PubMed2006

Monitoring tablet surface roughness during the film coating process.

The purpose of this study was to evaluate the change of surface roughness and the development of the film during the film coating process using laser profilometer roughness measurements, SEM imaging, and energy dispersive X-ray (EDX) analysis. Surface roughness and texture changes developing during the process of film coating tablets were studied by noncontact laser profilometry and scanning electron microscopy (SEM). An EDX analysis was used to monitor the magnesium stearate and titanium dioxide of the tablets. The tablet cores were film coated with aqueous hydroxypropyl methylcellulose, and the film coating was performed using an instrumented pilot-scale side-vented drum coater. The SEM images of the film-coated tablets showed that within the first 30 minutes, the surface of the tablet cores was completely covered with a thin film. The magnesium signal that was monitored by SEM-EDX disappeared after ~15 to 30 minutes, indicating that the tablet surface was homogeneously covered with film coating. The surface roughness started to increase from the beginning of the coating process, and the increase in the roughness broke off after 30 minutes of spraying. The results clearly showed that the surface roughness of the tablets increased until the film coating covered the whole surface area of the tablets, corresponding to a coating time period of 15 to 30 minutes (from the beginning of the spraying phase). Thereafter, the film only became thicker. The methods used in this study were applicable in the visualization of the changes caused by the film coating on the tablet surfaces.

Coated Materials, Biocompatible↗

PubMed2006

Multivariate data analysis as a fast tool in evaluation of solid state phenomena.

A thorough understanding of solid state properties is of growing importance. It is often necessary to apply multiple techniques offering complementary information to fully understand the solid state behavior of a given compound and the relations between various polymorphic forms. The vast amount of information generated can be overwhelming and the need for more effective data analysis tools is well recognized. The aim of this study was to investigate the use of multivariate data analysis, in particular principal component analysis (PCA), for fast analysis of solid state information. The data sets analyzed covered dehydration phenomena of a set of hydrates followed by variable temperature X-ray powder diffractometry and Raman spectroscopy and the crystallization of amorphous lactose monitored by Raman spectroscopy. Identification of different transitional states upon the dehydration enabled the molecular level interpretation of the structural changes related to the loss of water, as well as interpretation of the phenomena related to the crystallization. The critical temperatures or critical time points were identified easily using the principal component analysis. The variables (diffraction angles or wavenumbers) that changed could be identified by the careful interpretation of the loadings plots. The PCA approach provides an effective tool for fast screening of solid state information.

Anti-Bacterial Agents↗

PubMed2006

Understanding processing-induced phase transformations in erythromycin-PEG 6000 solid dispersions.

Since the quality and performance of a pharmaceutical solid formulation depend on solid state of the drug and excipients, a thorough investigation of potential processing-induced transformations (PITs) of the ingredients is required. In this study, the physical phenomena taking place during formulation of erythromycin (EM) dihydrate solid dispersions with polyethylene glycol (PEG) 6000 by melting were investigated. PITs were monitored in situ using variable temperature X-ray powder diffraction (VT-XRPD), differential scanning calorimetry (DSC), and hot-stage microscopy (HSM). Possible intermolecular interactions between the drug and polymer in the solid state were further studied by Fourier transform infrared (FTIR) spectroscopy. While in the absence of PEG the dehydration was the only transformation observed, hot-melt processing with the polymer caused the drug to undergo multiple phase transformations (EM dihydrate --> EM dehydrate --> EM anhydrate). This alteration in phase behavior of EM was attributed to the ability of PEG in promoting nucleation and crystal growth of the EM anhydrate through a solvent-mediated route. In situ monitoring of solid dispersion formation, especially by VT-XRPD and HSM, enabled both early-stage detection of phase transformations during the hot-melt processing and better process understanding.

Chemistry, Pharmaceutical↗

PubMed2006

In situ measurement of solvent-mediated phase transformations during dissolution testing.

In this study, solvent-mediated phase transformations of theophylline (TP) and nitrofurantoin (NF) were measured in a channel flow intrinsic dissolution test system. The test set-up comprised simultaneous measurement of drug concentration in the dissolution medium (with UV-Vis spectrophotometry) and measurement of the solid-state form of the dissolving solid (in situ with Raman spectroscopy). The solid phase transformations were also investigated off-line with scanning electron microscopy. TP anhydrate underwent a transformation to TP monohydrate, and NF anhydrate (form beta) to NF monohydrate (form II). Transformation of TP anhydrate to TP monohydrate resulted in a clear decrease in the dissolution rate, while the transformation of NF anhydrate (form beta) to NF monohydrate (form II) could not be linked as clearly to changes in the dissolution rate. The transformation of TP was an order of magnitude faster than that of NF. The presence of a water absorbing excipient, microcrystalline cellulose, was found to delay the onset of the transformation of TP anhydrate. Combining the measurement of drug concentration in the dissolution medium with the solid phase measurement offers a deeper understanding of the solvent-mediated phase transformation phenomena during dissolution.

Microscopy, Electron, Scanning↗

PubMed2005

Physical changes of beta-sitosterol crystals in oily suspensions during heating.

The aim of this research was to describe the thermal behavior of beta-sitosterol crystals in oil-suspensions with a focus on the role of water during heating. The suspensions were prepared by recrystallization in order to achieve a microcrystalline particle size. The structural changes together with the mechanical properties of the suspensions during heating were studied by using variable temperature X-ray powder diffractometry (VT-XRPD), differential scanning calorimetry (DSC), and dynamic mechanical analysis (DMA). Hydrated beta-sitosterol crystals in an oil-suspension dehydrated, despite the composition of the suspensions, at low temperatures. At high beta-sitosterol concentration, the monohydrate crystal form changed partially to a hemihydrated form, and when only a small amount of water was initially incorporated, the hemihydrate crystal form dehydrated to a mostly anhydrate crystal form. The released water, which was immiscible in the surrounding oil, caused the recrystallization of hydrated beta-sitosterol during cooling. This procedure indicated a reversible dehydration process. Structural and thermal analysis of beta-sitosterol crystals in suspensions, together with mechanical analysis made it possible to understand various physical changes during heating.

Chemical Phenomena↗

PubMed2005

Excipient selection can significantly affect solid-state phase transformation in formulation during wet granulation.

Phase transformations in formulations can lead to instability in physicochemical, biopharmaceutical, and processing properties of products. The influences of formulation design on the optimal dosage forms should be specified. The aim here was to investigate whether excipients with different water sorption behavior affect hydrate formation of nitrofurantoin in wet masses. Nitrofurantoin anhydrate was used as a hydrate-forming model drug, and 4 excipients with different water-absorbing potential (amorphous low-substituted hydroxypropylcellulose, modified maize starch, partially amorphous silicified microcrystalline cellulose, and crystalline alpha-lactose monohydrate) were granulated with varying amounts of purified water. Off-line evaluation of wet masses containing nitrofurantoin anhydrate and excipient (1:1) was performed using an X-ray powder diffractometer (XRPD) and near-infrared spectroscopy, and drying phase was evaluated by variable temperature XRPD. Only amorphous excipient in the formulation retarded hydrate formation of an active pharmaceutical ingredient (API) at high water contents. Hygroscopic partially crystalline excipient hindered hydrate formation of API at low water contents. Crystalline excipient was unable to control hydrate formation of API. The character of excipient affects the stability of formulation. Thus, correct selection of excipients for the formulation can control processing-induced phase transitions and improve the storage stability of the final dosage form.

Chemistry, Pharmaceutical↗

PubMed2005

Pellet manufacturing by extrusion-spheronization using process analytical technology.

The aim of this study was to investigate the phase transitions occurring in nitrofurantoin and theophylline formulations during pelletization by extrusion-spheronization. An at-line process analytical technology (PAT) approach was used to increase the understanding of the solid-state behavior of the active pharmaceutical ingredients (APIs) during pelletization. Raman spectroscopy, near-infrared (NIR) spectroscopy, and X-ray powder diffraction (XRPD) were used in the characterization of polymorphic changes during the process. Samples were collected at the end of each processing stage (blending, granulation, extrusion, spheronization, and drying). Batches were dried at 3 temperature levels (60 degrees C, 100 degrees C, and 135 degrees C). Water induced a hydrate formation in both model formulations during processing. NIR spectroscopy gave valuable real-time data about the state of water in the system, but it was not able to detect the hydrate formation in the theophylline and nitrofurantoin formulations during the granulation, extrusion, and spheronization stages because of the saturation of the water signal. Raman and XRPD measurement results confirmed the expected pseudopolymorphic changes of the APIs in the wet process stages. The relatively low level of Raman signal with the theophylline formulation complicated the interpretation. The drying temperature had a significant effect on dehydration. For a channel hydrate (theophylline), dehydration occurred at lower drying temperatures. In the case of isolated site hydrate (nitrofurantoin), dehydration was observed at higher temperatures. To reach an understanding of the process and to find the critical process parameters, the use of complementary analytical techniques are absolutely necessary when signals from APIs and different excipients overlap each other.

Chemistry, Pharmaceutical↗

PubMed2005

Characterization of polymorphic solid-state changes using variable temperature X-ray powder diffraction.

The aim of this study was to use variable temperature X-ray powder diffraction (VT-XRPD) to understand the solid-state changes in the pharmaceutical materials during heating. The model compounds studied were sulfathiazole, theophylline and nitrofurantoin. This study showed that the polymorph form of sulfathiazole SUTHAZ01 was very stable and SUTHAZ02 changed as a function of temperature to SUTHAZ01. Theophylline monohydrate changed via its metastable form to its anhydrous form during heating and nitrofurantoin monohydrate changed via amorphous form to its anhydrous form during heating. The crystallinity of SUTHAZ01, SUTHAZ02 and theophylline monohydrate were very high and stable. Nitrofurantoin monohydrate was also very crystalline at room temperature but during heating at lower temperatures the crystallinity decreased and started to increase strongly at the temperature where the sample had changed to the anhydrous form. The average crystallite size of sulfathiazole samples varied only a little during heating. The average crystallite size of both theophylline and nitrofurantoin monohydrate decreased during heating. However, the average crystallite size of nitrofurantoin monohydrate returned back to starting size at higher temperatures. These analyses showed that VT-XRPD can be used to effectively characterize polymorphic changes during heating.

Nitrofurantoin↗

PubMed2005

IR spectroscopy together with multivariate data analysis as a process analytical tool for in-line monitoring of crystallization process and solid-state analysis of crystalline product.

Crystalline product should exist in optimal polymorphic form. Robust and reliable method for polymorph characterization is of great importance. In this work, infra red (IR) spectroscopy is applied for monitoring of crystallization process in situ. The results show that attenuated total reflection Fourier transform infra red (ATR-FTIR) spectroscopy provides valuable information on process, which can be utilized for more controlled crystallization processes. Diffuse reflectance Fourier transform infra red (DRIFT-IR) is applied for polymorphic characterization of crystalline product using X-ray powder diffraction (XRPD) as a reference technique. In order to fully utilize DRIFT, the application of multivariate techniques are needed, e.g., multivariate statistical process control (MSPC), principal component analysis (PCA) and partial least squares (PLS). The results demonstrate that multivariate techniques provide the powerful tool for rapid evaluation of spectral data and also enable more reliable quantification of polymorphic composition of samples being mixtures of two or more polymorphs. This opens new perspectives for understanding crystallization processes and increases the level of safety within the manufacture of pharmaceutics.

Algorithms↗

PubMed2005

Use of in-line near-infrared spectroscopy in combination with chemometrics for improved understanding of pharmaceutical processes.

High shear granulation is a complex unit operation with several interacting process parameters. No generally accepted real-time in-line tools are available to gain insight into this process, and in practice, a highly experienced process formulator and operator are needed to develop a wet granulated solid dosage form. In this study, the use of in-line near-infrared (NIR) spectroscopy as a process analytical tool for high shear granulation was investigated. In combination with principal component-based methods, process analysis of three separate phases of high shear wet granulation (mixing, spraying, and wet massing) was facilitated. Critical information, both chemical and physical, was collected during processing. Chemical information included the homogeneity of the formulation and the amount of water in wet mass. In addition, physical information related to the particle size of granules was extracted. Principal component loadings were fully interpreted to validate the conclusions drawn from scores and predictions. Thus NIR spectroscopy could be used to determine the end points of the three subphases of high shear wet granulation and, as such, provide a fast in-line quality control tool.

Cellulose↗

PubMed2005

Role of water in the physical stability of solid dosage formulations.

The interaction of moisture with pharmaceutical solids is highly crucial to an understanding of water-based processes, for example, manufacturing processes or prediction of solid dosage form stability and shelf life. Both the active pharmaceutical ingredient (API) and excipients in the formulation have different moisture sorption properties that can result in unexpected processing-induced phase transitions and they can affect solid-state phase transitions in the final dosage forms. The character of excipient effects on the stability of formulation. Phase transformations in formulations can lead to instability in physicochemical, biopharmaceutical, and processing properties of products. The aim of the present study was to investigate the water sorption properties of different excipients, model the sorption isotherms, examine the phase transitions, and identify differences of excipients in solid dosage form stability using dynamic vapor sorption analysis, near-infrared spectroscopy, and X-ray diffraction methods. The thermal processing was carried out with a variable temperature X-ray powder diffractometer to compare the dehydration behavior of wet excipients and evaluate solid-state properties during heating. These results showed that despite some limitations, moisture sorption isotherms of excipients are useful in predicting solid-state stability, interactions at early stages of formulation development, and effects of moisture on physicochemical properties of the final dosage forms.

Cellulose↗

PubMed2005

Use of roughness maps in visualisation of surfaces.

In this study we will present a new method to describe surface roughness. This method builds a roughness map of the studied area. The roughness map can give information of localised roughness. The test surfaces used in the evaluation of the method were tablets, which were made of lactose monohydrate, theophylline anhydrate, sodium chloride and potassium chloride. The roughness determinations were made by a laser profilometer. The new matrix method gives detailed roughness maps, which are able to show local variations in surface roughness values and provide an illustrative picture of the heterogeneity of surface roughness of various materials.

Imaging, Three-Dimensional↗

PubMed2005

Batch cooling crystallization and pressure filtration of sulphathiazole: the influence of solvent composition.

Currently there is a great interest in new process analytical approaches to increase the process understanding of pharmaceutical unit operations. In the present study, the influence of the solvent composition on the material properties and, further, on the filtration characteristics, of different crystal suspensions obtained through an unseeded batch-cooling-crystallization process was studied. Sulphathiazole, which is an antibiotic agent with multiple polymorphic forms, was produced by performing laboratory-scale cooling crystallization experiments from five different mixtures of water and propan-1-ol (n-propanol). The size, shape and polymorphic composition of the crystals produced were characterized with a scanning electron microscope, with a novel automated image analyser and with an X-ray powder diffractometer. All of the monitored crystal properties were found to clearly differ between the samples obtained from different solvents. The crystals produced in the batch-cooling-crystallization experiments were separated from the crystallizing solvents using a batch-type pressure Nutsche filter, and the filtration characteristics of the suspensions were evaluated on the basis of average filter-cake porosities and average specific cake resistances, which were determined from the experimentally obtained filtration data. Comparison between the calculated filtration characteristics revealed that considerable differences existed between the different suspensions, and it could therefore be concluded that the pressure-filtration process was influenced by the composition of the crystallizing solvent. The filterability of all the studied sulphathiazole suspensions was considered to be rather good on the basis of the relatively low cake porosities (0.51-0.63), which were accompanied with low average specific cake resistances [(8.7 x 10(7))-(1.2 x 10(9)) m/kg].

1-Propanol↗

PubMed2005

Improved understanding of factors contributing to quantification of anhydrate/hydrate powder mixtures.

Different spectroscopic approaches have proved to be excellent analytical tools for monitoring process-induced transformations of active pharmaceutical ingredients during pharmaceutical unit operations. In order to use these tools effectively, it is necessary to build calibration models that describe the relationship between the amount of each solid-state form of interest and the spectroscopic signal. In this study, near-infrared (NIR) and Raman spectroscopic methods have been evaluated for the quantification of hydrate and anhydrate forms in pharmaceutical powders. Process type spectrometers were used to collect the data and the role of the sampling procedure was examined. Multivariate regression models were compared with traditional univariate calibrations and special emphasis was placed on data treatment prior to multivariate modeling by partial least squares (PLS). It was found that the measured sample volume greatly affected the performance of the model whereby the calibrations were significantly improved by utilizing a larger sampling area. In addition, multivariate regression did not always improve the predictability of the data compared to univariate analysis. The data treatment prior to multivariate modeling had a significant influence on the quality of predictions with standard normal variate transformation generally proving to be the best preprocessing method. When the appropriate sampling techniques and data analysis methods were utilized, both NIR and Raman spectroscopy were found to be suitable methods for the quantification of anhydrate/hydrate in powder systems, and thus the method of choice will depend on the conditions in the process under investigation.

Computer Systems↗

PubMed2004

Visualization of a pharmaceutical unit operation: wet granulation.

Recent developments in the field of process engineering and manufacturing sciences enable a new level of process understanding. However, extracting this understanding from increasing amounts of information is challenging. The aim of this study was to create a process vector from a model process describing all relevant information and, by that means, create a tool for combining and visualizing this information. Physical (impeller torque and temperature) and chemical (near-infrared spectroscopy) information from a small-scale high-shear granulation was used in the process vector. The vectors created were visualized by two different methods: principal component analysis (PCA) and the self-organizing map (SOM). None of the individual measurement techniques were able to describe the state of the process alone, although they provided important information about the process. By combining the data and visualizing it, an overview could be achieved. The SOM approach had two advantages over the PCA: it presented the results in terms of the original variables and enabled the analysis of nonlinear responses. However, both visualization methods could be used to describe the progress of the process and to increase the level of process understanding.

Chemistry, Pharmaceutical↗

PubMed2004

Comparison of the effects of two drying methods on polymorphism of theophylline.

Processing-induced transformations in drug formulation may induce adverse biopharmaceutical changes in the finished product. During the drying phase of wet granulation, theophylline monohydrate transforms either the stable (form I), or a polymorphic, metastable (form I(*)) form of anhydrous theophylline. We investigated the effect of two drying methods (multichamber microscale fluid bed dryer MMFD) or variable temperature X-ray powder diffractometer (VT-XRPD) on the relative amounts of the different theophylline forms remaining in the dried granules. Granules were analyzed using XRPD and near-infrared spectroscopy. Form I(*) was the predominant form of theophylline after drying at 40-50 degrees C with both drying techniques. Although drying at temperatures over 50 degrees C produced mostly form I, more than 20% of form I(*) remained even at 90 degrees C when drying in MMFD. In these conditions, humidity had little influence on the amount of form I(*) in the granules. In contrast, drying in a VT-XRPD at 60 degrees C produced form I already during the first 15min. Using additional drying methods, including MMFD, during the preformulation stage can be more informative about the possible polymorphic transformations and their underlying mechanisms, such as triboelectrification or recrystallization, in drug ingredients during the manufacturing process.

Chemistry, Pharmaceutical↗

PubMed2004

New perspectives for visual characterization of pharmaceutical solids.

The utilization of descriptive image information in pharmaceutical powder technology is rather limited. Consequently, the development of this discipline is a challenge within physical characterization of pharmaceutical solids. The aim of this study was to develop and evaluate an inventive visual characterization approach for monitoring the granule growth in a fluidized-bed granulation process and to use the generated image information in the prediction of tabletting behavior of granules. Surface images of samples from 34 granulations were continuously captured during the spraying and drying phases of the process and particle size distributions were determined. The gray scale difference matrix (GSDM) was derived from two surface images taken in controlled illumination conditions. The particle size calculation from the surface images was based on a multivariate Partial Least Square (PLS) model between the GSDM and sieve analysis measurements. The image information of the end-point samples was also evaluated with respect to tabletting behavior of the granules produced. Principal component analysis (PCA) was used for data visualization. The introduced approach was suitable in particle size measurements of granules during all process phases and in the monitoring of different kinds of granule growth behavior. The visual inspection of the granule samples was powerful, enabling representational batch-to-batch comparisons. The tabletting behavior of the granules could be predicted directly from particle size information generated from the surface images. PCA as a projection method was efficient in data visualization. Development of process analytical technologies (PAT) aims at improving the efficiency of processes. The presented visual characterization approach can be an effective process analytical tool in particle size analysis also enabling the evaluation of the further product quality in the end of the granulation process. The idea of characterization of bulk surface images opens new perspectives for characterization of pharmaceutical solids.

Particle Size↗