NIR Spectroscopy Applications in the Development of a Compacted Multiparticulate System for Modified Release

The purpose of this study was to utilize near-infrared spectroscopy and chemical imaging to characterize extrusion-spheronized drug beads, lipid-based placebo beads, and modified release tablets prepared from blends of these beads. The tablet drug load (10.5–19.5 mg) of theophylline (2.25 mg increments) and cimetidine (3 mg increments) could easily be differentiated using univariate analyses. To evaluate other tablet attributes (i.e., compression force, crushing force, content uniformity), multivariate analyses were used. Partial least squares (PLS) models were used for prediction and principal component analysis (PCA) was used for classification. The PLS prediction models (R ² > 0.98) for content uniformity of uncoated compacted theophylline and cimetidine beads produced the most robust models. Content uniformity data for tablets with drug content ranging between 10.5 and 19.5 mg showed standard error of calibration (SEC), standard error of cross-validation, and standard error of prediction (SEP) values as 0.31, 0.43, and 0.37 mg, and 0.47, 0.59, and 0.49 mg, for theophylline and cimetidine, respectively, with SEP/SEC ratios less than 1.3. PCA could detect blend segregation during tableting for preparations using different ratios of uncoated cimetidine beads to placebo beads (20:80, 50:50, and 80:20). Using NIR chemical imaging, the 80:20 formulations showed the most pronounced blend segregation during the tableting process. Furthermore, imaging was capable of quantitating the cimetidine bead content among the different blend ratios. Segregation testing (ASTM D6940-04 method) indicated that blends of coated cimetidine beads and placebo beads (50:50 ratio) also tended to segregate.     

Acoustic-resonance spectrometry as a process analytical technology for the quantification of active pharmaceutical ingredient in semi-solids

The purpose of this study was to demonstrate acoustic resonance spectrometry (ARS) as an alternative process analytical technology to near infrared (NIR) spectroscopy for the quantification of active pharmaceutical ingradient (API) in semi-solids such as creams, gels, ointments, and lotions. The ARS used for this research was an inexpensive instrument constructed from readily available parts. Acoustic-resonance spectra were collected with a frequency spectrum from 0 to 22.05 KHz. NIR data were collected from 1100 to 2500 nm. Using 1-point net analyte signal (NAS) calibration, NIR for the API (colloidal oatmeal [CO]) gave anr ² prediction accuracy of 0.971, and a standard error of performance (SEP) of 0.517%CO. ARS for the API resulted in anr ² of 0.983 and SEP of 0.317%CO. NAS calibration is compared with principal component regression. This research demonstrates that ARS can sometimes outperform NIR spectrometry and can be an effective analytical method for the quantification of API in semi-solids. ARS requires no sample preparation, provides larger penetration depths into lotions than optical techniques, and measures API concentrations faster and more accurately. These results suggest that ARS is a useful process analytical technology (PAT). Published: July 14, 2006     

Near‐infrared spectroscopic evaluation of lyophilized viral vaccine formulations

This article examines the applicability of near‐infrared spectroscopy (NIRS) to evaluate the virus state in a freeze‐dried live, attenuated vaccine formulation. Therefore, this formulation was freeze‐dried using different virus volumes and after applying different pre‐freeze‐drying virus treatments (resulting in different virus states): (i) as used in the commercial formulation; (ii) without antigen (placebo); (iii) concentrated via a centrifugal filter device; and (iv) stressed by 96 h exposure to room temperature. Each freeze‐dried product was measured directly after freeze‐drying with NIR spectroscopy and the spectra were analyzed using principal component analysis (PCA). Herewith, two NIR spectral regions were evaluated: (i) the 7300–4000 cm^?1 region containing the amide A/II band which might reflect information on the coated proteins of freeze‐dried live, attenuated viruses; and (ii) the C–H vibration overtone regions (10,000–7500 and 6340–5500 cm^?1) which might supply information on the lipid layer surrounding the freeze‐dried live, attenuated viruses. The different pre‐freeze‐drying treated live, attenuated virus formulations (different virus states and virus volumes) resulted in different clusters in the scores plots resulting from the PCA of the collected NIR spectra. Secondly, partial least squares discriminant analysis models (PLS‐DA) were developed and evaluated, allowing classification of the freeze‐dried formulations according to virus pretreatment. The results of this study suggest the applicability of NIR spectroscopy for evaluating live, attenuated vaccine formulations with respect to their virus pretreatment and virus volume. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29:1573–1586, 2013     

Multivariate Analysis of Phenol in Freeze-Dried and Spray-Dried Insulin Formulations by NIR and FTIR

Dehydration is a commonly used method to stabilise protein formulations. Upon dehydration, there is a significant risk the composition of the formulation will change especially if the protein formulation contains volatile compounds. Phenol is often used as excipient in insulin formulations, stabilising the insulin hexamer by changing the secondary structure. We have previously shown that it is possible to maintain this structural change after drying. The aim of this study was to evaluate the residual phenol content in spray-dried and freeze-dried insulin formulations by Fourier transform infrared (FTIR) spectroscopy and near infrared (NIR) spectroscopy using multivariate data analysis. A principal component analysis (PCA) and partial least squares (PLS) projections were used to analyse spectral data. After drying, there was a difference between the two drying methods in the phenol/insulin ratio and the water content of the dried samples. The spray-dried samples contained more water and less phenol compared with the freeze-dried samples. For the FTIR spectra, the best model used one PLS component to describe the phenol/insulin ratio in the powders, and was based on the second derivative pre-treated spectra in the 850–650 cm⁻¹ region. The best PLS model based on the NIR spectra utilised three PLS components to describe the phenol/insulin ratio and was based on the standard normal variate transformed spectra in the 6,200–5,800 cm⁻¹ region. The root mean square error of cross validation was 0.69% and 0.60% (w/w) for the models based on the FTIR and NIR spectra, respectively. In general, both methods were suitable for phenol quantification in dried phenol/insulin samples.     

Effects of plantain and corn starches on the mechanical and disintegration properties of paracetamol tablets

The effects of plantain starch obtained from the unripe fruit of the plantMusa paradisiaca L. (Musaceae) on the mechanical and disintegration properties of paracetamol tablets have been investigated in comparison with the effects of corn starch BP using a 2³ factorial experimental design. The individual and combined effects of nature of starch binder (N), concentration of starch binder (C), and the relative density of tablet (RD) on the tensile strength (TS), brittle fracture index (BFI), and disintegration time (DT) of the tablets were investigated. The ranking of the individual effects on TS was RD>C≫N, on BFI was C≫RD>N and on DT was N>C>RD. The ranking for the interaction effects on TS and DT was N-C≫N-RD>C-RD, while that on BFI was N-C≫C-RD>N-RD. Changing nature of starch from a “low” (plantain starch) to a “high” (corn starch) level, increasing the concentration of starch binding agent from 2.5% to 10.0% wt/wt, and increasing relative density of the tablet from 0.80 to 0.90, led to increase in the values of TS and DT, but a decrease in BFI. Thus, tablets containing plantain starch had lower tensile strength and disintegration time values than those containing corn starch, but showed better ability to reduce the lamination and capping tendency in paracetamol tablet formulation. The interaction between N and C was significantly (P<.001) higher than those between N and RD and between C and RD. There is therefore the need to carefully choose the nature (N) and concentration (C) of starch used as binding agent in tablet formulations to obtain tablets of desired bond strength and disintegration properties. Furthermore, plantain starch could be useful as an alternative binding agent to cornstarch, especially where faster disintegration is required and the problems of lamination and capping are of particular concern. Published: October 22, 2005     

Application of NIR Spectroscopy Coupled with PLS Regression for Quantification of Total Polyphenol Contents from the Fruit and Aerial Parts of Citrullus colocynthis

Introduction

Citrullus colocynthis (L.) Schrad is extensively used to treat diabetes, obesity, fever, cancer, amenorrhea, jaundice, leukemia, rheumatism, and respiratory diseases. Chemical studies have indicated the presence of several cucurbitacins, flavones, and other polyphenols in this plant. These phytochemical constituents are responsible for the interesting antioxidant and other biological activities of C. colocynthis.

Objective

In the present study, for the first time, near infrared (NIR) spectroscopy coupled with partial least square (PLS) regression analysis was used to quantify the polyphenolic phytochemicals of C. colocynthis.

Methodology

The fruit and aerial parts of the C. colocynthis were extracted individually in methanol followed by fractionation in n‐hexane, chloroform, ethyl acetate, n‐butanol, and water. Near infrared (NIR) spectra were obtained in absorption mode in the wavelength range 700–2500 nm. The PLS regression model was then built from the obtained spectral data to quantify the total polyphenol contents in the selected plant samples.

Results

The PLS regression model obtained had a R² value of 99% with a 0.98 correlationship value and a good prediction with a root mean square error of prediction (RMSEP) value of 1.89% and correlation of 0.98. These results were further confirmed through UV–vis spectroscopy and it is found that the ethyl acetate fraction has the maximum value for polyphenol contents (101.7 mg/100 g; NIR, 100.4 mg/100 g; UV–vis).

Conclusions

The polyphenolic phytochemicals of the fruit and aerial parts of C. colocynthis have been quantified successfully by using multivariate analysis in a non‐destructive, economical, precise, and highly sensitive method, which uses very simple sample preparation. Copyright © 2017 John Wiley & Sons, Ltd.     

Compressional Behavior of a Mixture of Granules Containing High Load of Phyllanthus niruri Spray-Dried Extract and Granules of Adjuvants: Comparison between Eccentric and Rotary Tablet Machines

The purpose of this paper was to evaluate the compressional behavior of granules containing high load of a Phyllanthus niruri spray-dried extract in eccentric (ETM) and rotary (RTM) tablet presses. Tablets were constituted by spray-dried extract granules (SDEG, 92%), excipient granules (EXCG, 7.92%), and magnesium stearate (0.08%). SDEG was obtained by dry granulation and EXCG, composed of microcrystalline cellulose (62.9%) and sodium starch glycolate (37.1%), by wet granulation. Particle size distribution was fixed between 0.250 and 0.850 mm. Tablets did not evidence any mechanical failures, such as lamination or capping, or anomalous weight variation in either tablet machine types. Upper and lower tablet surface photomicrographs from ETM and RTM tablets showed differences in porosity and texture. Different RTM speeds suggested the visco-plastic behavior of the formulation, since, by slowing down rotation speeds, the tensile strength of the tablets increased significantly, but the porosity and disintegration time were not affected. Tablets produced in RTM showed lower friability and porosity than ETM tablets, which did not reflect on higher tensile strength. The EXCG distribution at upper and lower surfaces from ETM and RTM tablets was quantified by image analysis and evaluated through statistical methods. Spray-dried extract release was not influenced by the type of equipment or operational conditions to which the compacts were submitted. Construction and operation differences between both tablet presses influenced the final product, since tablets with similar tensile strength, made by distinct tablet machines, exhibited different quality parameters.     

Dry granulation and compression of spray-dried plant extracts

The purpose of this research was to evaluate the influence of dry granulation parameters on granule and tablet properties of spray-dried extract (SDE) fromMaytenus ilicifolia, which is widely used in Brazil in the treatment of gastric disorders. The compressional behavior of the SDE and granules of the SDE was characterized by Heckel plots. The tablet properties of powders, granules, and formulations containing a high extract dose were compared. The SDE was blended with 2% magnesium stearate and 1% colloidal silicon dioxide and compacted to produce granules after slugging or roll compaction. The influences of the granulation process and the roll compaction force on the technological properties of the granules were studied. The flowability and density of spray-dried particles were improved after granulation. Tablets produced by direct compression of granules showed lower crushing strength than the ones obtained from nongranulated material. The compressional analysis by Heckel plots revealed that the SDE undergoes plastic deformation with a very low tendency to rearrangement at an early stage of compression. On the other hand, the granules showed an intensive rearrangement as a consequence of fragmentation and rebounding. However, when the compaction pressure was increased, the granules showed plastic deformation. The mean yield pressure values showed that both granulation techniques and the roll compaction force were able to reduce the material's ability to undergo plastic deformation. Finally, the tablet containing a high dose of granules showed a close dependence between crushing strength and the densification degree of the granules (ie, roll compaction force). Published: October 14, 2005     

Galacto‐oligosaccharides and lactulose as protectants against desiccation of Lactobacillus delbrueckii subsp. bulcaricus

Lactobacillus delbrueckii subsp. bulgaricus CIDCA 333 was dehydrated on desiccators containing silica gel in the presence of 20% w/w of two types of galacto‐oligosaccharides (GOS Biotempo and GOS Cup Oligo H‐70^®) and lactulose, until no changes in water desorption were detected. After rehydration, bacterial growth was monitored at 37°C by determining: (a) the absorbance at 600 nm and (b) the near infrared spectra (NIR). Principal component analysis (PCA) was then performed on the NIR spectra of samples dehydrated in all conditions. A multiparametric flow cytometry assay was carried out using carboxyfluorescein diacetate and propidium iodide probes to determine the relative composition of damaged, viable, and dead bacteria throughout the growth kinetics. The absorbance at 600 nm and the position of the second derivative band at ～1370 nm were plotted against the time of incubation. The efficiency of the protectants was GOS Biotempo > GOS Cup Oligo H‐70^® > lactulose. The better protectant capacity of GOS Biotempo was explained on the basis of the lower contribution of damaged cells immediately after rehydration (t = 0). PCA showed three groups along PC1, corresponding to the lag, exponential and stationary phases of growth, which explained 99% of the total variance. Along PC2, two groups were observed, corresponding to damaged or viable cells. The results obtained support the use of NIR to monitor the recovery of desiccated microorganisms in real time and without the need of chemical reagents. The use of GOS and lactulose as protectants in dehydration/rehydration processes was also supported. © 2014 American Institute of Chemical Engineers Biotechnol. Prog., 30:1231–1238, 2014     

Assessment of ATR‐NIR and ATR‐MIR spectroscopy as an analytical tool for the quantification of the total polyphenols in Dendrobium huoshanense

In this study, the potentiality of applying attenuated total reflectance near‐infrared (ATR‐NIR) and attenuated total reflectance mid‐infrared (ATR‐MIR) techniques combined with a partial least squares (PLS) regression technology to quantify the total polyphenols (TPs) in Dendrobium huoshanense (DHS) was investigated and compared. The real TP contents in the DHS samples were analysed using methods of reference. The capability of the two IR spectroscopic techniques to quantify the TPs in DHS was assessed by the root‐mean‐square error of calibration (RMSEC) and determination coefficients (R²). The results showed that both NIR and MIR might be used as a fast and simple tool to replace traditional chemical assays for the determination of the TP contents in DHS, and the best NIR model showed slightly better prediction performance [root‐mean‐square error of prediction (RMSEP): 0.307, R²: 0.9122, ratio performance deviation (RPD): 4.43] than the best MIR model (RMSEP: 0.440, R²: 0.9069, RPD: 3.09). Results from this study indicated that both the NIR and MIR models could be used to quantify the TP in DHS, and ATR‐NIR appeared to be the more predominant and more robust technique for the quantification of the TP in DHS.     

Optimization of tablets containing a high dose of spray-dried plant extract: A technical note

Optimization of CSD and CMC-Na in tablet formulations containing a high dose of SDE fromM ilicifolia was performed by central composite design (CCD) and response surface methodology (RSM). The study demonstrated that CSD affected mainly the hardness and friability, while CMC-Na modified the disintegration times. The optimum formula for minimum disintegration time and friability, and maximum crushing strength, was found to contain 1.2% (wt/wt) of CSD and 5.0% (wt/wt) of CMC-Na. At these conditions, the tablet shows a crushing strength of 107.9 N, a friability of 0.56% (wt/wt), and a maximum disintegration time of 6.8 minutes.     

Exploring the Use of Near Infrared (NIR) Reflectance Spectroscopy to Predict Starch Pasting Properties in Whole Grain Barley

This study aimed to evaluate the ability of using near infrared reflectance (NIR) spectroscopy to predict parameters generated by the rapid visco analyser (RVA) in whole grain barley samples to further study starch pasting characteristics in a breeding program. A total of 130 whole grain barley samples from the University of Adelaide germplasm collection, harvested over three seasons (2009, 2010 and 2011) were analysed using both NIR and RVA instruments and calibrations developed using partial least squares (PLS) regression. The coefficient of determination in cross validation (R ²) and the standard error in cross validation (SECV) were 0.88 [SECV?=?477.5 (RVU?=?rapid visco units)] for peak viscosity (PV), 0.82 (SECV?=?635.5 RVU) for trough (THR), 0.92 (SECV?=?190.4 RVU) for breakdown (BKD), 0.61 (SECV?=?151.1 RVU) for setback (SET), 0.84 (SECV?=?698.0 RVU) for final viscosity (FV), 0.70 (SECV?=?0.54 s) for time to peak (TTP) and 0.36 (SECV?=?2.2 min) for pasting temperature (PT). We have demonstrated that NIR spectroscopy shows promise as a rapid, non-destructive method to measure PV in whole grain barley. In this context, NIR spectroscopy has the potential to significantly reduce analytical time and cost for screening novel lines for starch properties for pasting properties.     

Once-daily tablet formulation and in vitro release evaluation of cefpodoxime using hydroxypropyl methylcellulose: A technical note

Summary and Conclusions  Decreasing the dose frequency of cefpodoxime proxetil increases patient compliance; patients prefer to take the drug once daily. It also improves the rate of bacterial killing and hastens the cure from the indications, and therefore increases compliance. The hydrophilic matrix of HPMC controlled the cefpodoxime proxetil release effectively for 24 hours; hence, the formulation can be considered as a once-daily sustained-release tablet of cefpodoxime proxetil. The formulation showed acceptable pharmacotechnical properties and assay requirements. In vitro dissolution studies indicated a sustained-release pattern throughout 24 hours of the study that was comparable to the theoretical release profile. Drug release kinetics indicated that drug release was best explained by Higuchi’s equation, as these plots showed the highest linearity (r ²=0.9734), but a close relationship was also noted with zero-order kinetics (r ²=0.9708). Korsmeyer’s plots indicated ann value of 0.57, which was indicative of an anomalous diffusion mechanism or diffusion coupled with erosion; hence, the drug release was controlled by more than one process. Hixson-Crowell plots indicated a change in surface area and diameter of the tablets with the progressive dissolution of the matrix as a function of time. Published: September 22, 2006     

Dry matter production and boron concentrations of vegetative and reproductive tissues of canola and sunflower plants grown in nutrient solution

Prediction of nitrogen (N) mineralization is important for specifying the optimum rate of N fertilizer for flooded rice at the time of sowing. To develop a predictive test, soils (0–0.1 m) were sampled from 22 farms throughout the rice-growing region of southern Australia over a 4-year period. Near infrared reflectance (NIR) spectra of the soils were compared with sixteen biological and chemical soil tests for the prediction of N-uptake by rice plants from these soils in the field and glasshouse. The aim of the study was to develop a soil-NIR calibration as an accurate, rapid and economical mineralization test. Nitrogen uptake by field-grown and glasshouse-grown plants was poorly correlated (r = 0.30), even though significant NIR calibrations were developed with both. Since N uptake by rice in the field was affected by varying weather and management, the field calibration is probably spurious. The calibration of soil NIR spectra with N uptake by glasshouse plants was satisfactory, with a standard error (SE) of 13 kg ha^–1 over a range of 11 – 95 kg ha^–1, and a correlation between calculated and measured N uptake (r = 0.87, P<0.001). An even better soil-NIR calibration was found with N-mineralization after 21 days of anaerobic incubation (SE 16 mg kg^–1, range 52–175 mg kg^–1). Analysis of the soil spectra showed that similar wavelengths were correlated with both plant-N uptake and mineralization. NIR spectroscopy shows considerable potential to predict soil N mineralization, and may assist future fertiliser decision support.     

Real‐time monitoring of high‐gravity corn mash fermentation using in situ raman spectroscopy

In situ Raman spectroscopy was employed for real‐time monitoring of simultaneous saccharification and fermentation (SSF) of corn mash by an industrial strain of Saccharomyces cerevisiae. An accurate univariate calibration model for ethanol was developed based on the very strong 883 cm^?1 C–C stretching band. Multivariate partial least squares (PLS) calibration models for total starch, dextrins, maltotriose, maltose, glucose, and ethanol were developed using data from eight batch fermentations and validated using predictions for a separate batch. The starch, ethanol, and dextrins models showed significant prediction improvement when the calibration data were divided into separate high‐ and low‐concentration sets. Collinearity between the ethanol and starch models was avoided by excluding regions containing strong ethanol peaks from the starch model and, conversely, excluding regions containing strong saccharide peaks from the ethanol model. The two‐set calibration models for starch (R² = 0.998, percent error = 2.5%) and ethanol (R² = 0.999, percent error = 2.1%) provide more accurate predictions than any previously published spectroscopic models. Glucose, maltose, and maltotriose are modeled to accuracy comparable to previous work on less complex fermentation processes. Our results demonstrate that Raman spectroscopy is capable of real time in situ monitoring of a complex industrial biomass fermentation. To our knowledge, this is the first PLS‐based chemometric modeling of corn mash fermentation under typical industrial conditions, and the first Raman‐based monitoring of a fermentation process with glucose, oligosaccharides and polysaccharides present. Biotechnol. Bioeng. 2013; 110: 1654–1662. © 2013 Wiley Periodicals, Inc.     

Discriminating pulmonary hypertension caused by monocrotaline toxicity from chronic hypoxia by near-infrared spectroscopy and multivariate methods of analysis

A new method has been developed for the determination of tissue pathology caused by chronic hypoxia and monocrotaline toxicity. The method is based on the use of near-infrared (NIR) spectrophotometry to measure spectra of lung tissue from normal chronic hypoxia (CH) and monocrotaline (MCT) models of pulmonary hypertension (PH), followed by analysis using multivariate methods, that is, principal component analysis (PCA) and partial least squares (PLS). Synergistic use of NIR with the PCA/PLS method makes it possible, for the first time, not only to divide different lung tissue samples into their respective groups (normal, CH, and MCT) but also to gain insight into mechanisms of PH caused by CH and MCT toxicity. Specifically, MCT metabolites and other hypertensive conditions are known to produce subtle and minor chemical changes in the compositions of tissue (e.g., proteins, carbohydrates, lipids). Although these changes were detected by the NIR technique, they were too small to be discerned through visual inspection of the spectra. However, they can be accurately classified and properly assigned by the PCA/PLS method. The fact that different tissue types can be accurately divided into their corresponding groups by the NIR and PCA/PLS methods suggests that chemical alterations and mechanisms of pulmonary vascular remodeling and PH induced by MCT are different from those induced by CH.     

Quality-by-Design III: Application of Near-Infrared Spectroscopy to Monitor Roller Compaction In-process and Product Quality Attributes of Immediate Release Tablets

The objective of this study is to use near-infrared spectroscopy (NIRS) coupled with multivariate chemometric models to monitor granule and tablet quality attributes in the formulation development and manufacturing of ciprofloxacin hydrochloride (CIP) immediate release tablets. Critical roller compaction process parameters, compression force (CF_t), and formulation variables identified from our earlier studies were evaluated in more detail. Multivariate principal component analysis (PCA) and partial least square (PLS) models were developed during the development stage and used as a control tool to predict the quality of granules and tablets. Validated models were used to monitor and control batches manufactured at different sites to assess their robustness to change. The results showed that roll pressure (RP) and CF_t played a critical role in the quality of the granules and the finished product within the range tested. Replacing binder source did not statistically influence the quality attributes of the granules and tablets. However, lubricant type has significantly impacted the granule size. Blend uniformity, crushing force, disintegration time during the manufacturing was predicted using validated PLS regression models with acceptable standard error of prediction (SEP) values, whereas the models resulted in higher SEP for batches obtained from different manufacturing site. From this study, we were able to identify critical factors which could impact the quality attributes of the CIP IR tablets. In summary, we demonstrated the ability of near-infrared spectroscopy coupled with chemometrics as a powerful tool to monitor critical quality attributes (CQA) identified during formulation development.KEY WORDS: chemometrics, crushing force, disintegration, near-infrared spectroscopy, partial least square, principal component analysis, quality by design, roller compaction     

Roller Compaction, Granulation and Capsule Product Dissolution of Drug Formulations Containing a Lactose or Mannitol Filler, Starch, and Talc

This study investigated the influence of excipient composition to the roller compaction and granulation characteristics of pharmaceutical formulations that were comprised of a spray-dried filler (lactose monohydrate or mannitol), pregelatinized starch, talc, magnesium stearate (1% w/w) and a ductile active pharmaceutical ingredient (25% w/w) using a mixed-level factorial design. The main and interaction effects of formulation variables (i.e., filler type, starch content, and talc content) to the response factors (i.e., solid fraction and tensile strength of ribbons, particle size, compressibility and flow of granules) were analyzed using multi-linear stepwise regression analysis. Experimental results indicated that roller compacted ribbons of both lactose and mannitol formulations had similar tensile strength. However, resulting lactose-based granules were finer than the mannitol-based granules because of the brittleness of lactose compared to mannitol. Due to the poor compressiblility of starch, increasing starch content in the formulation from 0% to 20% w/w led to reduction in ribbon solid fraction by 10%, ribbon tensile strength by 60%, and granule size by 30%. Granules containing lactose or more starch showed less cohesive flow than granules containing mannitol and less starch. Increasing talc content from 0% to 5% w/w had little effect to most physical properties of ribbons and granules while the flow of mannitol-based granules was found improved. Finally, it was observed that stored at 40 °C/75% RH over 12 weeks, gelatin capsules containing lactose-based granules had reduced dissolution rates due to pellicle formation inside capsule shells, while capsules containing mannitol-based granules remained immediate dissolution without noticeable pellicle formation.     

Design of Experiments-Based Monitoring of Critical Quality Attributes for the Spray-Drying Process of Insulin by NIR Spectroscopy

Moisture content and aerodynamic particle size are critical quality attributes for spray-dried protein formulations. In this study, spray-dried insulin powders intended for pulmonary delivery were produced applying design of experiments methodology. Near infrared spectroscopy (NIR) in combination with preprocessing and multivariate analysis in the form of partial least squares projections to latent structures (PLS) were used to correlate the spectral data with moisture content and aerodynamic particle size measured by a time of flight principle. PLS models predicting the moisture content were based on the chemical information of the water molecules in the NIR spectrum. Models yielded prediction errors (RMSEP) between 0.39% and 0.48% with thermal gravimetric analysis used as reference method. The PLS models predicting the aerodynamic particle size were based on baseline offset in the NIR spectra and yielded prediction errors between 0.27 and 0.48 μm. The morphology of the spray-dried particles had a significant impact on the predictive ability of the models. Good predictive models could be obtained for spherical particles with a calibration error (RMSECV) of 0.22 μm, whereas wrinkled particles resulted in much less robust models with a Q² of 0.69. Based on the results in this study, NIR is a suitable tool for process analysis of the spray-drying process and for control of moisture content and particle size, in particular for smooth and spherical particles.KEY WORDS: moisture content, multivariate analysis, NIR, particle size, spray-drying     

Prediction of Tablet Film-coating Thickness Using a Rotating Plate Coating System and NIR Spectroscopy

The purpose of this research was to create a calibration model based on near-infrared (NIR) spectroscopy data obtained during a small-scale coating process to predict in-line the coating layer thickness of tablets coated in a side-vented drum coater. The developed setup for the small-scale coating process consisted of a rotating plate with 20 tablets molds that pass a spraying unit, a heating unit, and an in-line NIR spectroscopy probe during one rotation. High-density polyethylene (HDPE) was compressed to flat-faced tablets, and these were coated with a sustained release coating suspension containing Kollicoat IR and Kollicoat SR 30D. The film thickness of these tablets was determined for each tablet individually with a digital micrometer. A calibration model of predicted film thickness versus real-film thickness using PLS regression was developed. This model was tested against in-line NIR data obtained from a coating drum process, in which biconvex HDPE tablets were film-coated with the same film-coating suspension. The model predicted a final coating thickness of 240 μm, while the measured average thickness (n = 100 tablets) was 210 μm. Taking into account the use of a different setup and differently shaped tablets, it was possible to predict the coating thickness with accuracy comparable to the one of the digital micrometer. Thus, the small-scale rotating plate system was found to be an efficient means of preparing calibration model for a tablet-coating drum process.