A generalized image analytical algorithm for investigating tablet disintegration.

Commonly used methods for analyzing tablet disintegration are based on visual observations and can thus be user-dependent. To address this, a generally applicable image analytical algorithm has been developed for machine vision-based quantification of tablet disintegration. The algorithm has been tested with a conventional immediate release tablet, as well as model compacts disintegrating mainly through erosion, and finally, with a polymeric slow-release system. Despite differences in disintegration mechanisms between these compacts, the developed image analytical algorithm demonstrated its general applicability through quantifying the extent of disintegration without adaptation of image analytical parameters. The reproducibility of the approach was estimated with commercial tablets, and further, it could differentiate a range of different model compacts. The developed image analytical algorithm mimics the human decision-making processes and the current experience-based visual evaluation of disintegration time. In doing so the algorithmic method allows a user-independent approach for development of the optimal tablet formulation as well as gaining an understanding on how the selection of excipients and manufacturing processes ultimately influences tablet disintegration.

Rapid Assessment of Tablet Film Coating Quality by Multispectral UV Imaging.

Chemical imaging techniques are beneficial for control of tablet coating layer quality as they provide spectral and spatial information and allow characterization of various types of coating defects. The purpose of this study was to assess the applicability of multispectral UV imaging for assessment of the coating layer quality of tablets. UV images were used to detect, characterize, and localize coating layer defects such as chipped parts, inhomogeneities, and cracks, as well as to evaluate the coating surface texture. Acetylsalicylic acid tablets were prepared on a rotary tablet press and coated with a polyvinyl alcohol-polyethylene glycol graft copolymer using a pan coater. It was demonstrated that the coating intactness can be assessed accurately and fast by UV imaging. The different types of coating defects could be differentiated and localized based on multivariate image analysis and Soft Independent Modeling by Class Analogy applied to the UV images. Tablets with inhomogeneous texture of the coating could be identified and distinguished from those with a homogeneous surface texture. Consequently, UV imaging was shown to be well-suited for monitoring of the tablet coating layer quality. UV imaging is a promising technique for fast quality control of the tablet coating because of the high data acquisition speed and its nondestructive analytical nature.

Multispectral UV imaging for fast and non-destructive quality control of chemical and physical tablet attributes.

Monitoring of tablet quality attributes in direct vicinity of the production process requires analytical techniques that allow fast, non-destructive, and accurate tablet characterization. The overall objective of this study was to investigate the applicability of multispectral UV imaging as a reliable, rapid technique for estimation of the tablet API content and tablet hardness, as well as determination of tablet intactness and the tablet surface density profile. One of the aims was to establish an image analysis approach based on multivariate image analysis and pattern recognition to evaluate the potential of UV imaging for automatized quality control of tablets with respect to their intactness and surface density profile. Various tablets of different composition and different quality regarding their API content, radial tensile strength, intactness, and surface density profile were prepared using an eccentric as well as a rotary tablet press at compression pressures from 20MPa up to 410MPa. It was found, that UV imaging can provide both, relevant information on chemical and physical tablet attributes. The tablet API content and radial tensile strength could be estimated by UV imaging combined with partial least squares analysis. Furthermore, an image analysis routine was developed and successfully applied to the UV images that provided qualitative information on physical tablet surface properties such as intactness and surface density profiles, as well as quantitative information on variations in the surface density. In conclusion, this study demonstrates that UV imaging combined with image analysis is an effective and non-destructive method to determine chemical and physical quality attributes of tablets and is a promising approach for (near) real-time monitoring of the tablet compaction process and formulation optimization purposes.

Chemical imaging and solid state analysis at compact surfaces using UV imaging.

Fast non-destructive multi-wavelength UV imaging together with multivariate image analysis was utilized to visualize distribution of chemical components and their solid state form at compact surfaces. Amorphous and crystalline solid forms of the antidiabetic compound glibenclamide, and microcrystalline cellulose together with magnesium stearate as excipients were used as model materials in the compacts. The UV imaging based drug and excipient distribution was in good agreement with hyperspectral NIR imaging. The UV wavelength region can be utilized in distinguishing between glibenclamide and excipients in a non-invasive way, as well as mapping the glibenclamide solid state form. An exploratory data analysis supported the critical evaluation of the mapping results and the selection of model parameters for the chemical mapping. The present study demonstrated that the multi-wavelength UV imaging is a fast process analytical technique with the potential for real-time monitoring of critical quality attributes.

Simultaneous UV imaging and raman spectroscopy for the measurement of solvent-mediated phase transformations during dissolution testing.

The current work reports the simultaneous use of UV imaging and Raman spectroscopy for detailed characterization of drug dissolution behavior including solid-state phase transformations during dissolution. The dissolution of drug substances from compacts of sodium naproxen in 0.1 HCl as well as theophylline anhydrate and monohydrate in water was studied utilizing a flow-through setup. The decreases in dissolution rates with time observed by UV imaging were associated with concomitant solid form changes detected by Raman spectroscopy. Sodium naproxen and theophylline anhydrate were observed to convert to the more stable forms (naproxen, and theophylline monohydrate) within approximately 5 min. Interestingly, the new approach revealed that three intermediate forms are involved in the dissolution process prior to the appearance of the neutral naproxen during dissolution in an acidic medium. The combination of UV imaging and Raman spectroscopy offers a detailed characterization of drug dissolution behavior in a time-effective and sample-sparing manner.

Current advances and future trends in characterizing poorly water-soluble drugs using spectroscopic, imaging and data analytical techniques.

A common feature of many new analytical techniques that allows fast and non-destructive analysis of poorly-water-soluble drug is that they generate a large amount of data with a multivariate character within a short time frame, which in turn highlights the need for advanced data analytical methods in extracting information from the complex data set. The current review critically examines how spectroscopy and imaging techniques can be utilized for fast and non-destructive characterization of solid state poorly water-soluble drug formulations. The first part of the present review describes the basics behind many of the currently used methods including Raman, near infrared (NIR), infrared (IR) spectroscopy and X-ray powder diffractometry in characterizing poorly water soluble drugs. Key emphasis was placed on a critical review of the currently used spectral preprocessing methods, and the influence of selected preprocessing on spectral data sets is exemplified. Further the existing uni- and multivariate spectral data analytical methods in analyzing complex spectral data sets are reviewed, covering estimation of spectral peak moments, peak modeling, variations of Principal Component Analysis (PCA), variations of Partial Least Squares (PLS) analysis and Multivariate Curve Resolution (MCR). The second part of the present review discusses hyperspectral imaging, UV imaging, optical microscopy imaging and process imaging methods suitable for characterization of poorly water-soluble solid state drug formulations. Image analytical techniques suitable for analyzing hyperspectral image data set are described. Further, the application of various image analytical techniques leading to the estimation of nucleation and crystal growth rates from polarized light microscopy is described.

Fuzzy Logic-based expert system for evaluating cake quality of freeze-dried formulations.

Freeze-drying of peptide and protein-based pharmaceuticals is an increasingly important field of research. The diverse nature of these compounds, limited understanding of excipient functionality, and difficult-to-analyze quality attributes together with the increasing importance of the biosimilarity concept complicate the development phase of safe and cost-effective drug products. To streamline the development phase and to make high-throughput formulation screening possible, efficient solutions for analyzing critical quality attributes such as cake quality with minimal material consumption are needed. The aim of this study was to develop a fuzzy logic system based on image analysis (IA) for analyzing cake quality. Freeze-dried samples with different visual quality attributes were prepared in well plates. Imaging solutions together with image analytical routines were developed for extracting critical visual features such as the degree of cake collapse, glassiness, and color uniformity. On the basis of the IA outputs, a fuzzy logic system for analysis of these freeze-dried cakes was constructed. After this development phase, the system was tested with a new screening well plate. The developed fuzzy logic-based system was found to give comparable quality scores with visual evaluation, making high-throughput classification of cake quality possible.

A case study of real-time monitoring of solid-state phase transformations in acoustically levitated particles using near infrared and Raman spectroscopy.

The objective of this study was to monitor the amorphous-to-crystalline solid-state phase transformation kinetics of the model drug ibuprofen with spectroscopic methods during acoustic levitation. Chemical and physical information was obtained by real-time near infrared (NIRS) and Raman spectroscopy measurements. The recrystallisation kinetic parameters (overall recrystallisation rate constant ß and the time needed to reach 50% of the equilibrated level t(50)), were determined using a multivariate curve resolution approach. The acoustic levitation device coupled with non-invasive spectroscopy enabled monitoring of the recrystallisation process of the difficult-to-handle (adhesive) amorphous sample. The application of multivariate curve resolution enabled isolation of the underlying pure spectra, which corresponded well with the reference spectra of amorphous and crystalline ibuprofen. The recrystallisation kinetic parameters were estimated from the recrystallisation profiles. While the empirical recrystallisation rate constant determined by NIR and Raman spectroscopy were comparable, the lag time for recrystallisation was significantly lower with Raman spectroscopy as compared to NIRS. This observation was explained by the high energy density of the Raman laser beam, which might have led to local heating effects of the sample and thus reduced the recrystallisation onset time. It was concluded that acoustic levitation with NIR and Raman spectroscopy combined with multivariate curve resolution allowed direct determination of the recrystallisation kinetics of amorphous drugs and thus is a promising technique for monitoring solid-state phase transformations of adhesive small-sized samples during the early phase of drug development.

Fast-track to a solid dispersion formulation using multi-way analysis of complex interactions.

Several factors with complex interactions influence the physical stability of solid dispersions, thus highlighting the need for efficient experimental design together with robust and simple multivariate model. Design of Experiments together with ANalysis Of VAriance (ANOVA) model is one of the central tools when establishing a design space according to the Quality by Design (QbD) approach. However, higher order interaction terms are often significant in these ANOVA models, making the final model difficult to interpret and understand. As this is ordinarily the purpose of applying ANOVA, it poses an obvious problem. In the current study, the GEneralized Multiplicative ANOVA (GEMANOVA) model is proposed as an alternative for the ANOVA model. Two complex multivariate data sets obtained by monitoring the physical stability of a solid dispersion with image analysis and X-ray powder diffraction (XRPD) as responses were subjected to GEMANOVA analysis. The results showed that the obtained GEMANOVA model was easier to interpret and understand than the additive ANOVA model. Furthermore, the GEMANOVA model has additional advantages such as the possibility of readily including multivariate responses (e.g., an entire spectral data set), model uniqueness, and curve resolution abilities.

A novel image analysis methodology for online monitoring of nucleation and crystal growth during solid state phase transformations.

This study focuses on the development of an automated image analysis method to extract information on nucleation and crystal growth from polarized light micrographs. Using the developed image analysis method, four parameters related to nucleation and crystal growth could be extracted from the images. These parameters were crystalline count (applied as a measure of nucleation), percentage area coverage, average equivalent diameter and average crystalline area (three last parameters applied as a measure for crystal growth). The developed image analysis method was used to investigate two pharmaceutically relevant case studies: first, nitrendipine antisolvent crystallization, and second, recrystallization of amorphous piroxicam solid dispersion in an aqueous environment. In both case studies, an amorphous-to-crystalline phase transformation were observed, which were successfully monitored using real-time Raman spectroscopy. For the both case studies, the parameters related to crystallization kinetics estimated by image analysis were in close agreement with the parameters estimated by Raman spectroscopy. The developed image analysis method proved to be a valuable tool for quantitative monitoring of nucleation and crystal growth with an obvious potential for high throughput screening.

Solvent-mediated amorphous-to-crystalline transformation of nitrendipine in amorphous particle suspensions containing polymers.

The amorphous-to-crystalline transformation of nitrendipine was investigated using Raman spectroscopy and X-ray powder diffraction (XRPD). The nucleation and growth rate of crystalline nitrendipine in a medium containing poly (vinyl alcohol) (PVA) and polyethylene glycol (PEG 200) were quantitatively determined using image analysis based on polarized light microscopy. The findings from the image analysis revealed that the transformation process occurred through the dissolution of amorphous drug precipitate followed by the nucleation and growth of the crystalline phase with the amorphous precipitate acting as a reservoir for maintaining the supersaturation. The rates of nucleation and crystal growth of nitrendipine decreased with an increase in PEG 200 concentration in organic phase from 0% to 75% (v/v). Increasing the PVA concentration in water phase from 0.1% to 1.0% (w/w) also decreased the rates of nucleation and crystal growth, however, an increase in PVA concentration from 1.0% to 2.0% (w/w) did not result in a further decrease in the rates of nucleation and crystal growth. An increase in drug concentrations in the organic phase from 10 mg/ml to 30 mg/ml led to faster nucleation rates. However, a further increase in drug concentration to 100mg/ml decelerated the growth of nitrendipine crystals. Combining image analysis of polarized light micrographs together with Raman spectroscopy and XRPD provided an in-depth insight into solid state transformations in amorphous nitrendipine suspensions.

Polymer-mediated anti-solvent crystallization of nitrendipine: monodispersed spherical crystals and growth mechanism.

PURPOSE: To investigate anti-solvent crystallization and growth mechanism of nitrendipine spherical crystals in an aqueous solution containing polymeric additives. METHODS: Size and shape of crystals were investigated using laser diffractometry, optical microscopy and scanning electron microscopy (SEM). Crystalline form was determined by X-ray powder diffractometer (XRPD). During crystal growth, morphological changes at different time points were observed using SEM. RESULTS: Morphology of nitrendipine crystals was affected by polymers and temperature. Monodispersed micro-spherical crystals were obtained when polyvinyl alcohol (PVA) and PEG 200 were present in crystallization medium at 2°C. During crystallization, large number of amorphous nanoparticles was first observed, followed by aggregation into a core for spherical crystals. Once crystalline state was achieved, rapid growth on core surface was observed with amorphous particles acting as a reservoir allowing formation of star-like particles with needle-like subunits. Spherical crystals were formed by filling the gap between needle-like distinct crystalline units of star-like templates with molecules from dissolved amorphous particles. CONCLUSIONS: Monodispersed nitrendipine spherical crystals were obtained using carefully controlled conditions. A mechanism for the nitrendipine spherical crystal growth is suggested. These findings provide a new insight into spherulitic crystallization of active pharmaceutical ingredients.

Influence of solvent evaporation rate and formulation factors on solid dispersion physical stability.

New chemical entities (NCEs) often show poor water solubility necessitating solid dispersion formulation. The aim of the current study is to employ design of experiments in investigating the influence of one critical process factor (solvent evaporation rate) and two formulation factors (PVP:piroxicam ratio (PVP:PRX) and PVP molecular weight (P(MW))) on the physical stability of PRX solid dispersion prepared by the solvent evaporation method. The results showed the rank order of an increase in factors contributing to a decrease in the extent of PRX nucleation being evaporation rate>PVP:PRX>P(MW). The same rank order was found for the decrease in the extent of PRX crystal growth in PVP matrices from day 0 up to day 12. However, after 12days the rank became PVP:PRX>evaporation rate>P(MW). The effects of an increase in evaporation rate and PVP:PRX ratio in stabilizing PRX were of the same order of magnitude, while the effect from P(MW) was much smaller. The findings were confirmed by XRPD. FT-IR showed that PRX recrystallization in the PVP matrix followed Ostwald's step rule, and an increase in the three factors all led to increased hydrogen bonding interaction between PRX and PVP. The present study showed the applicability of the Quality by Design approach in solid dispersion research, and highlights the need for multifactorial analysis.

Particle size dependence of polymorphism in spray-dried mannitol.

The purpose of this project was to investigate the polymorphic variation of spray-dried mannitol model formulations as a function of particle size. Spray-dried powders with varying mannitol polymorphs were produced by adjusting process parameters, using co-solvent and adding a model protein (lysozyme). The obtained dry powders were dispersed into different size fractions using a Next Generation Pharmaceutical Impactor. The mannitol polymorphs in the different size fractions were analyzed using X-ray powder diffraction (XRPD), Fourier transform near infrared (FT-NIR) and Raman spectroscopy. Chemometrics was applied to interpret the FT-NIR and Raman spectra. Different spray-dried mannitol systems were established in this study, which contain mixtures of α- and ß-mannitol. The XRPD, FT-NIR and Raman studies showed that the use of ethanol as a co-solvent increased the amount of α-mannitol in the smaller particles. The addition of low levels of lysozyme resulted in more α-mannitol in the smaller particles, while an increased content of lysozyme in spray-dried mannitol system resulted in more ß-mannitol in the smaller particle size fraction. In conclusion spray-drying of mannitol based formulations can result in variation in the solid state composition of mannitol as a function of particle size. This finding may be clinically relevant and underlines the need for proper process control of inhalable dry powder produced by spray-drying.

Influence of temperature on solvent-mediated anhydrate-to-hydrate transformation kinetics.

PURPOSE: To achieve an in-depth understanding of the underlying mechanism of the acceleration or deceleration effect of temperature on solvent-mediated anhydrate-to-hydrate phase transformation. METHODS: The effect of temperature on the phase transformation rate and onset time of two model compounds was investigated using in situ Raman spectroscopy. The thermodynamic driving force of the phase transformation (e.g. supersaturation) at different temperatures was determined by measuring the solubility of the anhydrate and the hydrate. RESULTS: Both acceleration and deceleration effects of temperature on the phase transformation were observed. The mechanism of these temperature effects was studied by exploring the influence of temperature on supersaturation level and crystallization kinetics. Increasing temperature usually leads to accelerated phase transformation kinetics, but it simultaneously decreases supersaturation, which has the opposite effect on the kinetics of the phase transformation. The overall effect of temperature on the phase transformation is therefore determined by the combined effects of supersaturation and temperature on the nucleation and crystal growth kinetics of the hydrate. CONCLUSIONS: By differentiating and comparing the effects of temperature and supersaturation on the anhydrate-to-hydrate phase transformation, a deeper understanding of the underlying principle of the acceleration and deceleration effects of temperature on the phase transformation has been achieved.