Multimodal Nonlinear Optical Imaging for Sensitive Detection of Multiple Pharmaceutical Solid-State Forms and Surface Transformations.

Two nonlinear imaging modalities, coherent anti-Stokes Raman scattering (CARS) and sum-frequency generation (SFG), were successfully combined for sensitive multimodal imaging of multiple solid-state forms and their changes on drug tablet surfaces. Two imaging approaches were used and compared: (i) hyperspectral CARS combined with principal component analysis (PCA) and SFG imaging and (ii) simultaneous narrowband CARS and SFG imaging. Three different solid-state forms of indomethacin-the crystalline gamma and alpha forms, as well as the amorphous form-were clearly distinguished using both approaches. Simultaneous narrowband CARS and SFG imaging was faster, but hyperspectral CARS and SFG imaging has the potential to be applied to a wider variety of more complex samples. These methodologies were further used to follow crystallization of indomethacin on tablet surfaces under two storage conditions: 30 °C/23% RH and 30 °C/75% RH. Imaging with (sub)micron resolution showed that the approach allowed detection of very early stage surface crystallization. The surfaces progressively crystallized to predominantly (but not exclusively) the gamma form at lower humidity and the alpha form at higher humidity. Overall, this study suggests that multimodal nonlinear imaging is a highly sensitive, solid-state (and chemically) specific, rapid, and versatile imaging technique for understanding and hence controlling (surface) solid-state forms and their complex changes in pharmaceuticals.

Simultaneous Comparison of Two Roller Compaction Techniques and Two Particle Size Analysis Methods.

A new dry granulation technique, gas-assisted roller compaction (GARC), was compared with conventional roller compaction (CRC) by manufacturing 34 granulation batches. The process variables studied were roll pressure, roll speed, and sieve size of the conical mill. The main quality attributes measured were granule size and flow characteristics. Within granulations also the real applicability of two particle size analysis techniques, sieve analysis (SA) and fast imaging technique (Flashsizer, FS), was tested. All granules obtained were acceptable. In general, the particle size of GARC granules was slightly larger than that of CRC granules. In addition, the GARC granules had better flowability. For example, the tablet weight variation of GARC granules was close to 2%, indicating good flowing and packing characteristics. The comparison of the two particle size analysis techniques showed that SA was more accurate in determining wide and bimodal size distributions while FS showed narrower and mono-modal distributions. However, both techniques gave good estimates for mean granule sizes. Overall, SA was a time-consuming but accurate technique that provided reliable information for the entire granule size distribution. By contrast, FS oversimplified the shape of the size distribution, but nevertheless yielded acceptable estimates for mean particle size. In general, FS was two to three orders of magnitude faster than SA.

High-Speed Intrinsic Dissolution Rate in One Minute Using the Single-Particle Intrinsic Dissolution Rate Method.

Intrinsic dissolution rate (IDR) has traditionally been determined from a constant surface area of a substance. Here we present an optofluidic single-particle intrinsic dissolution rate (SIDR) method, by means of which real-time determination of IDR from continuously changing effective surface areas of dissolving individual microparticles, is possible. The changing surface area of the individual microparticles is characterized through continuous random orientation 3D particle morphology characterization during the dissolution process. Using noninvasive optical monitoring and nonspecific image analysis, we determined IDRs of a diverse set of substances from individual pure-substance microparticles (14-747 µg) with an average relative standard deviation of 9.4%. A linear fit between SIDR and literature equilibrium solubility values (R(2) = 0.999) was achieved and kinetic solubility equivalent SIDRs were obtained, for all substances, in as little as 1 min. Such miniaturized methods could become valuable tools in drug discovery, by providing resource sparing higher quality data acquisition means to replace current high-throughput solubility methods.

On-chip optofluidic single-particle method for rapid microscale equilibrium solubility screening of biologically active substances.

Solubility is the primary physicochemical property determining the absorption and bioavailability of substances. Here, we present an optofluidic single-particle technique for microscale equilibrium solubility determination, based on on-chip hydrodynamic particle trapping and optical particle size monitoring. The method combines the rapidity, universality, and substance sparing nature of physical analysis, with the accuracy traditionally associated with chemical analysis. Applying the diffusion layer theory, we determined the equilibrium solubility from individual pure substance microparticles of as little as 14 µg in initial mass, in a matter of seconds to minutes. The reduction in time and substance consumption, when compared to the golden standard method, is above 2 orders of magnitude. With a simultaneous improvement above 3-fold in accuracy of the solubility data, the applicability of optofluidics based analytics for small-scale high-throughput quantitative solubility and biological activity screening is demonstrated.

Fast tablet tensile strength prediction based on non-invasive analytics.

In this paper, linkages between tablet surface roughness, tablet compression forces, material properties, and the tensile strength of tablets were studied. Pure sodium halides (NaF, NaBr, NaCl, and NaI) were chosen as model substances because of their simple and similar structure. Based on the data available in the literature and our own measurements, various models were made to predict the tensile strength of the tablets. It appeared that only three parameters-surface roughness, upper punch force, and the true density of material-were needed to predict the tensile strength of a tablet. Rather surprising was that the surface roughness alone was capable in the prediction. The used new 3D imaging method (Flash sizer) was roughly a thousand times quicker in determining tablet surface roughness than traditionally used laser profilometer. Both methods gave practically analogous results. It is finally suggested that the rapid 3D imaging can be a potential in-line PAT tool to predict mechanical properties of tablets in production.

Towards more reliable automated multi-dose dispensing: retrospective follow-up study on medication dose errors and product defects.

To date, little is known on applicability of different types of pharmaceutical dosage forms in an automated high-speed multi-dose dispensing process. The purpose of the present study was to identify and further investigate various process-induced and/or product-related limitations associated with multi-dose dispensing process. The rates of product defects and dose dispensing errors in automated multi-dose dispensing were retrospectively investigated during a 6-months follow-up period. The study was based on the analysis of process data of totally nine automated high-speed multi-dose dispensing systems. Special attention was paid to the dependence of multi-dose dispensing errors/product defects and pharmaceutical tablet properties (such as shape, dimensions, weight, scored lines, coatings, etc.) to profile the most suitable forms of tablets for automated dose dispensing systems. The relationship between the risk of errors in dose dispensing and tablet characteristics were visualized by creating a principal component analysis (PCA) model for the outcome of dispensed tablets. The two most common process-induced failures identified in the multi-dose dispensing are predisposal of tablet defects and unexpected product transitions in the medication cassette (dose dispensing error). The tablet defects are product-dependent failures, while the tablet transitions are dependent on automated multi-dose dispensing systems used. The occurrence of tablet defects is approximately twice as common as tablet transitions. Optimal tablet preparation for the high-speed multi-dose dispensing would be a round-shaped, relatively small/middle-sized, film-coated tablet without any scored line. Commercial tablet products can be profiled and classified based on their suitability to a high-speed multi-dose dispensing process.

Direct compression of cellulose and lignin isolated by a new catalytic treatment.

Tablet compression of softwood cellulose and lignin prepared by a new catalytic oxidation and acid precipitation method were investigated and compared with the established pharmaceutical direct compression excipients. Catalytic pretreated softwood cellulose (CPSC) and lignin (CPSL) were isolated from pine wood (Pinus sylvestris). The compaction studies were carried out with an instrumented eccentric tablet machine. The plasticity and elasticity of the materials under compression were evaluated using force-displacement treatment and by determining characteristic plasticity (PF) and elasticity (EF) factors. With all biomaterials studied, the PF under compression decreased exponentially as the compression force increased. The compression force applied in tablet compression did not significantly affect the elasticity of CPSC and microcrystalline cellulose (MCC) while the EF values for softwood lignins increased as compression force increased. CPSL was clearly a less plastically deforming and less compactable material than the two celluloses (CPSC and MCC) and hardwood lignin. CPSL presented deformation and compaction behaviour almost identical to that of lactose monohydrate. In conclusion, the direct tablet compression behaviour of native lignins and celluloses can greatly differ from each other depending on the source and isolation method used.

Rapid formulation screening with a Multipart Microscale Fluid bed Powder processor.

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.

3D simulation of internal tablet strength during tableting.

This study presents a new approach to model powder compression during tableting. The purpose of this study is to introduce a new discrete element simulation model for particle-particle bond formation during tablet compression. This model served as the basis for calculating tablet strength distribution during a compression cycle. Simulated results were compared with real tablets compressed from microcrystalline cellulose/theophylline pellets with various compression forces. Simulated and experimental compression forces increased similarly. Tablet-breaking forces increased with the calculated strengths obtained from the simulations. The calculated bond strength distribution inside the tablets showed features similar to those of the density and pressure distributions in the literature. However, the bond strength distributions at the center of the tablets varied considerably between individual tablets.

Rapid particle size measurement using 3D surface imaging.

The present study introduces a new three-dimensional (3D) surface image analysis technique in which white light illumination from different incident angles is used to create 3D surfaces with a photometric approach. The three-dimensional features of the surface images created are then used in the characterization of particle size distributions of granules. This surface image analysis method is compared to sieve analysis and a particle sizing method based on spatial filtering technique with nearly 30 granule batches. The aim is also to evaluate the technique in flowability screening of granular materials. Overall, the new 3D imaging approach allows a rapid analysis of large amounts of sample and gives valuable visual information on the granule surfaces in terms of surface roughness and particle shape.

Effects of spray drying on physicochemical properties of chitosan acid salts.

The effects of spray-drying process and acidic solvent system on physicochemical properties of chitosan salts were investigated. Chitosan used in spray dryings was obtained by deacetylation of chitin from lobster (Panulirus argus) origin. The chitosan acid salts were prepared in a laboratory-scale spray drier, and organic acetic acid, lactic acid, and citric acid were used as solvents in the process. The physicochemical properties of chitosan salts were investigated by means of solid-state CP-MAS (13)C nuclear magnetic resonance (NMR), X-ray powder diffraction (XRPD), differential scanning calorimetry, and Fourier transform infrared spectrometry (FTIR) and near-infrared spectroscopy. The morphology of spray-dried chitosan acid salts showed tendency toward higher sphericity when higher temperatures in a spray-drying process were applied. Analysis by XRPD indicated that all chitosan acid salts studied were amorphous solids. Solid-state (13)C NMR spectra revealed the evidence of the partial conversion of chitosan acetate to chitin and also conversion to acetyl amide form which appears to be dependent on the spray-drying process. The FTIR spectra suggested that the organic acids applied in spray drying may interact with chitosan at the position of amino groups to form chitosan salts. With all three chitosan acid salts, the FTIR bands at 1,597 and 1,615 cm(-1) were diminished suggesting that -NH groups are protonated. The FTIR spectra of all chitosan acid salts exhibited ammonium and carboxylate bands at 1,630 and 1,556 cm(-1), respectively. In conclusion, spray drying is a potential method of preparing acid salts from chitosan obtained by deacetylation of chitin from lobster (P. argus) origin.

The effect of relative humidity and formulation variables on chewable xylitol-sorbitol tablets.

Changing relative humidity levels challenge the manufacturing of chewable xylitol-sorbitol based tablets. The aim of the study is to investigate how the formulation of chewable xylitol-sorbitol tablets affects the properties of the powder blends and the tablets in an environment of different relative humidity levels. In all, 30 batches containing different ratios of sorbitol, xylitol and magnesium stearate were prepared at three different relative humidity levels. Powder blends were made into tablets using an instrumented eccentric tableting machine. To demonstrate the effect of variables on powder blend and tablet properties, multiple linear regression analysis was performed. It was found that xylitol-sorbitol powder blends and tablets benefitted from the large amount of magnesium stearate, and the high lubricant level negatively affected the quality of the tablets only at high relative humidity. In the presence of high environmental humidity, the amount of sorbitol in the powder mixture must be limited in order to prevent sticking whereas at low relative humidity, higher content of sorbitol is needed to decrease the friability of tablets. Results indicate that alternating relative humidity levels truly challenge the production of xylitol-sorbitol based tablets and if the humidity is not controllable, there is a need for additional filler-binders.

Effect of colloidal silicon dioxide and moisture on powder flow properties: Predicting in-process performance using image-based analysis.

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.

Ultrasound-assisted powder-coating technique to improve content uniformity of low-dose solid dosage forms.

An ultrasound-assisted powder-coating technique was used to produce a homogeneous powder formulation of a low-dose active pharmaceutical ingredient (API). The powdered particles of microcrystalline cellulose (MCC; Avicel® PH-200) were coated with a 4% m/V aqueous solution of riboflavin sodium phosphate, producing a uniform drug layer on the particle surfaces. It was possible to regulate the amount of API in the treated powder. The thickness of the API layer on the surface of the MCC particles increased near linearly as the number of coating cycles increased, allowing a precise control of the drug content. The tablets (n = 950) prepared from the coated powder showed significantly improved weight and content uniformity in comparison with the reference tablets compressed from a physical binary powder mixture. This was due to the coated formulation remaining uniform during the entire tabletting process, whereas the physical mixture of the powders was subject to segregation. In conclusion, the ultrasound-assisted technique presented here is an effective tool for homogeneous drug coating of powders of irregular particle shape and broad particle size distribution, improving content uniformity of low-dose API in tablets, and consequently, ensuring the safe delivery of a potent active substance to patients.

Application of crustacean chitin as a co-diluent in direct compression of tablets.

A "simplex-centroid mixture design" was used to study the direct-compression properties of binary and ternary mixtures of chitin and two cellulosic direct-compression diluents. Native milled and fractioned (125-250 microm) crustacean chitin of lobster origin was blended with microcrystalline cellulose, MCC (Avicel PH 102) and spray-dried lactose-cellulose, SDLC Cellactose (composed of a spray-dried mixture of alpha-lactose monohydrate 75% and cellulose powder 25%). An instrumented single-punch tablet machine was used for tablet compactions. The flowability of the powder mixtures composed of a high percentage of chitin and SDLC was clearly improved. The fractioned pure chitin powder was easily compressed into tablets by using a magnesium stearate level of 0.1% (w/w) but, as the die lubricant level was 0.5% (w/w), the tablet strength collapsed dramatically. The tablets compressed from the binary mixtures of MCC and SDLC exhibited elevated mechanical strengths (>100 N) independent of the die lubricant level applied. In conclusion, fractioned chitin of crustacean origin can be used as an abundant direct-compression co-diluent with the established cellulosic excipients to modify the mechanical strength and, consequently, the disintegration of the tablets. Chitin of crustacean origin, however, is a lubrication-sensitive material, and this should be taken into account in formulating direct-compression tablets of it.

Image-based characterization of powder flow to predict the success of pharmaceutical minitablet manufacturing.

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%.

Predicting particle size during fluid bed granulation using process measurement data.

In this study, a new concept for particle size prediction during the fluid bed granulation is presented. Using the process measurements data obtained from a design of experimental study, predictive partial least squares models were developed for spraying and drying phases. Measured and calculated process parameters from an instrumented fluid bed granulation environment were used as explaining factors, whereas an in-line particle size data determined by spatial filtering technique were used as response. Modeling was carried out by testing all possible combinations of two to six process parameters (factors) of the total of 41 parameters. Eleven batches were used for model development and four batches for model testing. The selected models predicted particle size (d50) well, especially during the spraying phase (Q2=0.86). While the measured in-line d50 data were markedly influenced by different process failures, e.g., impaired fluidization activity, the predicted data remained more consistent. This introduced concept can be applied in fluid bed granulation processes if the granulation environment is soundly instrumented and if reliable real-time particle size data from the design of experiment batches are retrieved for the model development.

Effective modification of particle surface properties using ultrasonic water mist.

The goal of the present study was to design a new technique to modify particle surface properties and, through that, to improve flowability of poorly flowing drug thiamine hydrochloride and pharmaceutical sugar lactose monohydrate of two different grades. The powdered particles were supplied by a vibratory feeder and exposed to an instantaneous effect of water mist generated from an ultrasound nebulizer. The processed and original powders were evaluated with respect to morphology (scanning electron microscopy, atomic force microscopy, and spatial filtering technique), flow, and solid state properties. It was found that rapid exposition of pharmaceutical materials by water mist resulted in the improvement of powder technical properties. The evident changes in flowability of coarser lactose were obviously due to smoothing of particle surface and decreasing in the level of fines with very slight increment in particle size. The changes in thiamine powder flow were mainly due to narrowing in particle size distribution where the tendency for better flow of finer lactose was related to surface and size modifications. The aqueous mist application did not cause any alteration of the crystal structures of the studied materials. The proposed water mist treatment technique appears to be a robust, rapid, and promising tool for the improvement of the technological properties of pharmaceutical powders.

Sugar end-capped poly-D,L-lactides as excipients in oral sustained release tablets.

Sugar end-capped poly-D,L-lactide (SPDLA) polymers were investigated as a potential release controlling excipient in oral sustained release matrix tablets. The SPDLA polymers were obtained by a catalytic ring-opening polymerization technique using methyl alpha-D-gluco-pyranoside as a multifunctional initiator in the polymerization. Polymers of different molecular weights were synthesized by varying molar ratios of monomer/catalyst. The matrix tablets were prepared by direct compression technique from the binary mixtures of SPDLA and microcrystalline cellulose, and theophylline was used as a model drug. The tablet matrices showed in vitro reproducible drug release profiles with a zero-order or diffusion-based kinetic depending on the SPDLA polymer grade used. Further release from the tablet matrices was dependent on the molecular weight of the SPDLA polymer applied. The drug release was the fastest with the lowest molecular weight SPDLA grade, and the drug release followed zero-order rate. With the higher molecular weight SPDLAs, more prolonged dissolution profiles for the matrix tablets (up to 8-10 h) were obtained. Furthermore, the prolonged drug release was independent of the pH of the dissolution media. In conclusion, SPDLAs are a novel type of drug carrier polymers applicable in oral controlled drug delivery systems.

Crystal morphology engineering of pharmaceutical solids: tabletting performance enhancement.

Crystal morphology engineering of a macrolide antibiotic, erythromycin A dihydrate, was investigated as a tool for tailoring tabletting performance of pharmaceutical solids. Crystal habit modification was induced by using a common pharmaceutical excipient, hydroxypropyl cellulose, as an additive during crystallization from solution. Observed morphology of the crystals was compared with the predicted Bravais-Friedel-Donnay-Harker morphology. An analysis of the molecular arrangements along the three dominant crystal faces [(002), (011), and (101)] was carried out using molecular simulation and thus the nature of the host-additive interactions was deduced. The crystals with modified habit showed improved compaction properties as compared with those of unmodified crystals. Overall, the results of this study proved that crystal morphology engineering is a valuable tool for enhancing tabletting properties of active pharmaceutical ingredients and thus of utmost practical value.