RESUMEN
The effect of colloidal silicon dioxide (CSD) on powder flow properties of poor-flowing excipient lactose 200 M was investigated. Binary mixtures of different ratios of CSD as glidant were examined using a modern image-based flow measuring technique. Special attention was placed to subtle variations in powder flow from small changes in glidant concentration (0.025% w/w). Understanding the modes of interaction of particles and their effects on flowability using the method predicted the die filling performance during tablet manufacture. In addition, the importance of moisture content on powder flow properties was empirically underlined. A more efficient range of CSD was detected from 0.10 to 0.50% w/w in most of the tested conditions, which revealed a significant improvement in powder flow performance compared to higher amounts typically handled in the pharmaceutical industry.
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Excipientes , Lactosa , Tamaño de la Partícula , Polvos , Dióxido de Silicio , ComprimidosRESUMEN
Powder flowability plays an important role in die filling during tablet manufacturing. The present study introduces a novel small-scale measuring technique for powder flow. Based on image analysis, the flow was defined depending on the variation of luminous intensity and the movement of powder inside the measurement cuvette. Using quantities around 100 mg it was possible to characterize a wide range of common pharmaceutical powders, especially in distinguishing subtle differences in flow caused by minor changes in samples characteristics. The method was compared with powder rheometry, which is widely used in the pharmaceutical literature, and showed a significant improvement in predicting the success of pharmaceutical minitablet manufacture (d = 5 mm). Tablet weight variation (RSD) was defined as the most efficient way to assess relevant powder flow behaviour in tablet production when using the novel device. The proposed method was distinguished from others by its ability to classify different grades of microcrystalline cellulose in the die-filling process. Subsequently, eight common pharmaceutical powders, both excipients and APIs, were properly ranked as a function of flowability based on their physical properties. The method showed a high repeatability, with a relative standard deviation not more than 10%.
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Celulosa/química , Química Farmacéutica/métodos , Reología/métodos , Celulosa/análisis , Predicción , Polvos , ComprimidosRESUMEN
BACKGROUND: Interactive response technologies are used in clinical trials to provide services such as automated randomization and medication logistics management. The objective of this article is to investigate the usage of telephone (Interactive Voice Response) and web (Interactive Web Response) interfaces of interactive response technologies at clinical investigator sites in clinical trials, to obtain information about the preferences of interactive response technology end users between the telephone and web interfaces, and to explore the relevance of the telephone interface in this setting. METHODS: The data consist of an online survey conducted in spring 2016 with clinical investigators, study nurses, and pharmacists in 13 countries. RESULTS: Ninety-eight percent of survey respondents preferred the web interface over the telephone interface, the most important reason being superior usability. However, the respondents indicated the usability of interactive response technology interfaces is not optimal, and lack of integration and consistency across systems is common. A vast majority of interactive response technology end users at clinical sites prefer to use the web interface over the telephone interface, but most also feel there would need to be a back-up system. CONCLUSIONS: Based on the results, it would be beneficial to improve the usability of the interactive response technology interfaces, and to increase consistency across systems from the current level. Support to and training of the users, as well as clarifying the responsibilities between sites and the sponsor should also be a focal point. Study sponsors should explore with interactive response technology service providers how removing the telephone interface would impact future studies, and whether there could be a more efficient means to achieve a reliable back-up to the web interface instead of a dedicated telephone interface.
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Ensayos Clínicos como Asunto/métodos , Internet , Estudios Multicéntricos como Asunto/métodos , Investigadores/psicología , Teléfono , Adulto , Factores de Edad , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Características de la Residencia , Factores Sexuales , Factores Socioeconómicos , Interfaz Usuario-Computador , Adulto JovenRESUMEN
We introduce atomic layer deposition (ALD) as a novel method for the ultrathin coating (nanolayering) of minitablets. The effects of ALD coating on the tablet characteristics and taste masking were investigated and compared with the established coating method. Minitablets containing bitter tasting denatonium benzoate were coated by ALD using three different TiO2 nanolayer thicknesses (number of deposition cycles). The established coating of minitablets was performed in a laboratory-scale fluidized-bed apparatus using four concentration levels of aqueous Eudragit® E coating polymer. The coated minitablets were studied with respect to the surface morphology, taste masking capacity, in vitro disintegration and dissolution, mechanical properties, and uniformity of content. The ALD thin coating resulted in minimal increase in the dimensions and weight of minitablets in comparison to original tablet cores. Surprisingly, ALD coating with TiO2 nanolayers decreased the mechanical strength, and accelerated the in vitro disintegration of minitablets. Unlike previous studies, the studied levels of TiO2 nanolayers on tablets were also inadequate for effective taste masking. In summary, ALD permits a simple and rapid method for the ultrathin coating (nanolayering) of minitablets, and provides nanoscale-range TiO2 coatings on porous minitablets. More research, however, is needed to clarify its potential in tablet taste masking applications.
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Comprimidos , Tecnología Farmacéutica/métodos , Ácidos Polimetacrílicos , Solubilidad , Gusto , TitanioRESUMEN
Both clodronate and bioactive glass are mostly used alone as treatment in various bone diseases but, they are also known to have beneficial effects in dental application. The same processes that lead to loss of bone can also result in alveolar bone loss. The object of this study was to define the optimal combination of clodronate and bioactive glass (BAG) to be used locally in dentistry. The evaluation was based on measurements and solid state properties obtained with pH, scanning electron microscopy (SEM), differential scanning calorimetric (DSC), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR) and Focused-ion beam (FIB) and energy dispersive X-ray spectroscopic (EDS) mapping. The results indicate that if too much calcium clodronate precipitation is formed, the activity of BAG is affected negatively. As there is more reaction surface to form calcium clodronate, similar to the amount of clodronate present, this reduces the bioactivity of BAG. Therefore, in dental treatment the most suitable BAG and clodronate combination product would have apatite (HA, hydroxyapatite) formation ability and amount of clodronate enough to enhance the bioactivity of BAG allowing HA formation. Based on combinations investigated, the one with 200mg clodronate and 1 g BAG with particle size 0.5-0.8 mm was chosen to be the most promising for local dental application.
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Pérdida de Hueso Alveolar/tratamiento farmacológico , Conservadores de la Densidad Ósea/química , Sustitutos de Huesos/química , Ácido Clodrónico/química , Vidrio/química , Periodontitis/tratamiento farmacológico , Conservadores de la Densidad Ósea/farmacología , Sustitutos de Huesos/farmacología , Rastreo Diferencial de Calorimetría , Precipitación Química , Química Farmacéutica , Ácido Clodrónico/farmacología , Cristalografía por Rayos X , Combinación de Medicamentos , Estudios de Factibilidad , Humanos , Concentración de Iones de Hidrógeno , Hidroxiapatitas/química , Microscopía Electrónica de Rastreo , Tamaño de la Partícula , Difracción de Polvo , Espectrometría por Rayos X , Espectroscopía Infrarroja por Transformada de Fourier , Propiedades de Superficie , Tecnología Farmacéutica/métodosRESUMEN
Bone tissue engineering is a rapidly growing area of research involving the use of bioactive glass (BG) alone and in combination with different materials. The objective of this study was to investigate the interaction of BG with clodronate. Characterisation of the interaction between BG and clodronate was undertaken using; scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), Fourier transform Raman spectroscopy and Fourier transform infrared spectroscopy (FTIR). The interaction was examined in vitro with respect to the ion exchange and surface modification on the surface of the bioactive glass in the combination product. The results showed clear ion exchange enhancement by clodronate. Additionally, this ion exchange was more extensive and long lasting in the combination product than in BG alone. Clodronate promotes the activity of the BG and a calcium clodronate precipitation is formed. It can be assumed that this solid combination could be used in clinical applications. Therefore, it can be concluded that clodronate makes a beneficial environment for BG and could enhance also the apatite formation of BG.
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Conservadores de la Densidad Ósea/química , Ácido Clodrónico/química , Vidrio/química , Sustitutos de Huesos/química , Intercambio Iónico , Microscopía Electrónica de Rastreo , Difracción de Polvo , Espectroscopía Infrarroja por Transformada de Fourier , Ingeniería de Tejidos , Difracción de Rayos XRESUMEN
PURPOSE: To study how water plasticization affects the molecular mobility and crystallization tendency of freeze-dried trehalose, sucrose, melibiose and cellobiose. METHODS: Freeze-dried disaccharides were subjected to different relative humidity atmospheres and their physical stabilities were evaluated. Lyophilizate water sorption tendencies and glass transition temperatures were modeled using Brunauer-Emmett-Teller (BET) and Gordon-Taylor (GT) equations, respectively. Sucrose and cellobiose crystallization tendencies were compared by using the concept of reduced crystallization temperature (RCT), and the molecular mobilities of trehalose and melibiose were compared by measuring their T(1)H relaxation time constants. RESULTS: Based on the BET and GT models, water sorption tendency and the resulting plasticizing effect were different in sucrose when compared to the other disaccharides. Trehalose and melibiose exhibited generally slower crystallization rates when compared to sucrose and cellobiose. Amorphous melibiose was shown to be particularly stable within the studied water content range, which may have partly been caused by its relatively slow molecular mobility. CONCLUSIONS: Slow amorphous-to-crystalline transition rate is known to be important for lyoprotecting excipients when formulating a robust drug product. The physical stabilities of amorphous trehalose and melibiose even with relatively high water contents might make their use advantageous in this respect compared to sucrose and cellobiose.
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Disacáridos/química , Plastificantes/química , Agua/química , Absorción , Cristalización , Almacenaje de Medicamentos , Liofilización/métodos , Humedad , Temperatura de TransiciónRESUMEN
The aim of this study was to investigate early formulation screening in small scale with a miniaturized fluid bed device. Altogether eight different batches were granulated in a Multipart Microscale Fluid bed Powder processor (MMFP) with constant process conditions using electrostatic atomization. Atomization voltage and granulation liquid flow rate were kept constant. Acid acetylsalicylic was used as model active pharmaceutical ingredient (API), lactose monohydrate, microcrystalline cellulose and polyvinylpyrrolidone were used as excipients. Granule size distributions were measured with spatial filtering technique. Friability test was performed by spinning granules in the mixer with glass beads. Compressibility of the granules was evaluated by tableting and the breaking force of the tablets was measured. Multivariate analysis, namely partial least squares regression and multilinear regression were applied to the data. It was possible to generate granules of different compositions rapidly employing MMFP with electrostatic atomization fast and acquire reliable and logical results with only small amount of material. However, a major challenge was to find suitable analytical methods for such small batches.
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Aspirina/química , Composición de Medicamentos/métodos , Excipientes/química , Polvos , Comprimidos/química , Celulosa/química , Lactosa/química , Tamaño de la Partícula , Povidona/química , Análisis de RegresiónRESUMEN
BACKGROUND: Use of external contractors is nowadays inevitable in the pharmaceutical industry. Therefore the amount of current good manufacturing practice audits has been increasing. During the audit, a large amount of items should be covered in a limited amount of time. Consequently, pharmaceutical companies should have systematic and effective ways to manage and prepare for the audits. This study is a continuation to the earlier study, where a tool for the preparation of cGMP audit was developed and its content was validated. The objective of this study was to evaluate the usefulness of the developed tool in audit preparation and during the actual cGMP audit. METHOD: Three qualitative research methods were used in this study (observation, interviews, and opinion survey). First, the validity of the information given through the tool was examined by comparing the responses to the actual conditions observed during the contract manufacturer audits (n = 15). Additionally the opinions of the contract manufacturers of the tool were gathered (n = 10) and the auditors were interviewed (n = 2). RESULTS: The developed tool was proven to be useful in audit preparation phase from both the auditor's and the contract manufacturers' point of view. Furthermore, using the tool can also save some time when performing the audit. CONCLUSION: The results show that using the tool can give significant support in audit preparation phase and also during the actual audit.
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Servicios Contratados , Industria Farmacéutica/métodos , Industria Farmacéutica/normas , Auditoría Administrativa/métodos , Auditoría Administrativa/normas , Adhesión a DirectrizRESUMEN
The aim of this study was to investigate the rheological properties, molecular mobility and crystallization tendency of pure citric acid and paracetamol or blends of them. Amorphous samples were produced by ethanol-evaporation or by melt-quenching. Enthalpy recovery, glass fragility and heat capacity were determined by differential scanning calorimetry (DSC). Other physical characterization methods were rheology and the crystallization tendency using X-ray powder diffraction (XRPD) and DSC. All the samples behaved as Newtonian liquids and they were fragile glasses. The 50/50 (w/w,%) blend had good physical stability upon consecutive shearing regardless of the preparation method. All the samples were stable for at least one year in dry conditions at -20 degrees C. The melt-produced blends containing 25% or 50% paracetamol were stable at least two years in dry ambient conditions. The good physical stability at ambient temperature cannot be explained by molecular mobility because molecular mobility of the model material is less than 100 s in ambient conditions. Thus other factors, such as the thermodynamic and crystallization driving forces or formation of degradation products, must determine the physical stability of the blends. The composition and processing method have an impact on the physical stability of the sample.
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Acetaminofén/química , Ácido Cítrico/química , Termodinámica , Rastreo Diferencial de Calorimetría , Química Farmacéutica/métodos , Cristalización , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Transición de Fase , Reología , Temperatura , Difracción de Rayos XRESUMEN
Using L-cysteine chewing gum to eliminate carcinogenic acetaldehyde in the mouth during smoking has recently been introduced. Besides its efficacy, optimal properties of the gum include stability of the formulation. However, only a limited number of studies exist on the compatibility of chewing gum excipients and stability of gum formulations. In this study we used the solid-state stability method, Fourier transform infrared spectroscopy and isothermal microcalorimetry to investigate the interactions between L-cysteine (as a free base or as a salt) and excipients commonly used in gum. These excipients include xylitol, sorbitol, magnesium stearate, Pharmagum S, Every T Toco and Smily 2 Toco. The influence of temperature and relative humidity during a three-month storage period on gum formulation was also studied. Cysteine alone was stable at 25 degrees C/60% RH and 45 degrees C/75% RH whether stored in open or closed glass ambers. As a component of binary mixtures, cysteine base remained stable at lower temperature and humidity but the salt form was incompatible with all the studied excipients. The results obtained with the different methods corresponded with each other. At high temperature and humidity, excipient incompatibility with both forms of cysteine was obvious. Such sensitivity to heat and humidity during storage was also seen in studies on gum formulations. It was also found that cysteine is sensitive to high pressure and increase in temperature induced by compression. The results suggest that the final product should be well protected from temperature and humidity and, for example, cooling process before compression should be considered.
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Anticarcinógenos/química , Goma de Mascar , Cisteína/química , Excipientes/química , Anticarcinógenos/administración & dosificación , Calorimetría , Cisteína/administración & dosificación , Incompatibilidad de Medicamentos , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Humedad , Presión , Espectroscopía Infrarroja por Transformada de Fourier , TemperaturaRESUMEN
Outsourcing is rapidly growing in the pharmaceutical industry. When the manufacturing activities are outsourced, control of the product's quality has to be maintained. One way to confirm contract manufacturer's GMP (Good Manufacturing Practice) compliance is auditing. Audits can be supported for instance by using GMP questionnaires. The objective of this study was to develop a tool for the audit preparation of pharmaceutical contract manufacturers and to validate its contents by using Delphi method. At this phase of the study the tool was developed for non-sterile finished product contract manufacturers. A modified Delphi method was used with expert panel consisting of 14 experts from pharmaceutical industry, authorities and university. The content validity of the developed tool was assessed by a Delphi questionnaire round. The response rate in Delphi questionnaire round was 86%. The tool consisted of 103 quality items, from which 90 (87%) achieved the pre-defined agreement rate level (75%). Thirteen quality items which did not achieve the pre-defined agreement rate were excluded from the tool. The expert panel suggested only minor changes to the tool. The results show that the content validity of the developed audit preparation tool was good.
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Algoritmos , Industria Farmacéutica/normas , Preparaciones Farmacéuticas/normas , Auditoría Administrativa , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
The purpose of this study was to compare impeller torque measurements and near-infrared (NIR) spectroscopy in the characterization of the water addition phase of a wet granulation process. Additionally, the effect of hydrate formation during granulation on the impeller torque was investigated. Anhydrous theophylline, alpha-lactose monohydrate, and microcrystalline cellulose (MCC) were used as materials for the study. The materials and mixtures of them were granulated using purified water in a small-scale high-shear mixer. The impeller torque was registered and NIR spectra of wet samples were recorded at-line. The torque and the NIR baseline-corrected water absorbances increased with increasing water content. A plateau in the NIR baseline-corrected water absorbances was observed for wet masses containing MCC. This was at the region of optimal water amount for granulation according to the torque results. In the case of anhydrous theophylline, the slope of baseline-corrected water absorbance values increased at the same water amount as the impeller torque started to increase. The hydrate formation of theophylline during granulation was observed as a slight decrease in the impeller torque. In addition, the hydrate formation during granulation affected the granulation liquid requirement. The liquid requirement was different for monohydrate formed during granulation compared to one formed in high relative humidity before the granulation. The results suggest that NIR spectroscopy may be applicable to process monitoring of wet granulation, also in cases where monitoring of impeller torque is difficult to apply.
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Espectroscopía Infrarroja Corta/métodos , Tecnología Farmacéutica/métodos , TorqueRESUMEN
The aim of the present study was to prepare controlled-release tablets of poorly-soluble drug, felodipine. Spray chilling was used to formulate the drug, the polar lipids and the hydrophilic polymers into solid dispersion microparticles, which were then compressed. The microparticles were characterised by Fourier transform infrared and Raman spectroscopies, X-ray powder diffraction, hot-stage microscopy, scanning electron microscopy, and image analysis. The crystallinity of felodipine had decreased in all the samples, and the amount of crystalline felodipine varied depending on the composition of the solid dispersion. The particles were spherical with the median particle diameter ranging from 20 to 35 microm. The addition of hydrophilic polymer into the matrix widened the particle size distribution and increased the amount of agglomerates. Most promising dissolution patterns were obtained from tablets containing glycerides; e.g. from Precirol ATO 5/Pluronic F127 tablets the release was of zero order.
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Preparaciones de Acción Retardada/química , Excipientes/química , Felodipino/química , Química Farmacéutica , Cristalización , Composición de Medicamentos , Microscopía/métodos , Tamaño de la Partícula , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría Raman , Comprimidos/análisis , Factores de Tiempo , Difracción de Rayos XRESUMEN
Formation of solid solution particles in the Solution Enhanced Dispersion by Supercritical fluids (SEDS) process from a model drug and two different types of carriers, mannitol and Eudragit E100 was evaluated. The crystal properties of samples and molecular interactions were investigated with DSC and FTIR, respectively. The effect of co-crystallisation of drug and mannitol on dissolution rate was studied. Even if a true one-phase solid dispersion was not obtained, the crystal structure of both drug and mannitol was mutually affected by the presence of the other. The drug was not in highly crystalline form in the co-precipitates. The interactions between the drug and mannitol could also be identified as hydrogen bonding between the amine or hydroxyl groups of the drug and the hydroxyl groups of mannitol. These interactions and changes in the crystal structure are probably directly related to the increase in the dissolution rate observed. A true solid solution was obtained when the drug was co-processed with Eudragit E100. A clear interaction between the acid hydroxyl group of the drug and the basic carbonyl group on the Eudragit E100 was observed. SEDS was shown to be an effective process for forming intimate blends and solid solutions for the drug and two different types of carriers.
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Portadores de Fármacos/química , Evaluación Preclínica de Medicamentos/métodos , Preparaciones Farmacéuticas/química , Tecnología Farmacéutica/métodos , Portadores de Fármacos/síntesis química , Manitol/síntesis química , Manitol/química , Preparaciones Farmacéuticas/síntesis química , Ácidos Polimetacrílicos/síntesis química , Ácidos Polimetacrílicos/química , SolubilidadRESUMEN
The Aerosizer is an instrument for time-of-flight measurement, which is widely used in particle size determinations. The results of various studies indicate that there are still some problems related to the optimization of the analysis conditions. In this study, the behaviour of a set of different kinds of pharmaceutical particles during Aerosizer measurements was studied. An Aerosizer LD equipment with an Aero-Disperser was validated with particle size standards. Volume particle size distributions of particles with different size and shape characteristics were determined (PVP, Celphere, lactose, a drug substance, PHB microparticles). The aim was to investigate the effects of the shear force and deagglomeration levels during the dispersion of the particles on the particle size distributions that were obtained. The results of this study indicate that the ability of the instrument to disperse particles is highly dependent on the properties of the materials. According to the validation measurements, the instrument gives accurate results for spherical, uncohesive particles. The capability of the dispersing unit to separate particles aerodynamically was well observed with PVP. Time-of-flight measurements were uncomplicated for relatively large particles, such as Celphere, which have little interaction with each other and with the instrument housing. For lactose, increasing shear force rates resulted in size distributions with larger particle sizes. In the case of the PHB microparticles the results indicated that the aggregates became smaller and particles were partly separated to primary particles with all shear force levels.
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Aerosoles/química , Nebulizadores y Vaporizadores , Celulosa/química , Diseño de Equipo , Humanos , Hidroxibutiratos/química , Lactosa/química , Tamaño de la Partícula , Poliésteres/química , Povidona/química , Prohibitinas , Reproducibilidad de los Resultados , Resistencia al CorteRESUMEN
The aim of the present study was to prepare controlled-release tablets of poorly-soluble drug, felodipine, and various erodable lipophilic excipients. Spray chilling was used to formulate the drug and the excipients into solid dispersion microparticles, which were then compressed. The microparticles were characterised by Fourier transform infrared spectroscopy, hot-stage microscopy, scanning electron microscopy, and image analysis. The amine and the carbonyl groups of felodipine formed hydrogen bonds with the carriers. The shape of the particles was spherical with the median particle diameter ranging from 25 to 35 microm. Surprisingly, the degree of crystallinity in felodipine and the ease of tablet disintegration played a more significant role on the felodipine dissolution rate than the matrix lipophilicity. Felodipine release rate was slowest from the least lipophilic tablets.