Quality by design, part I: application of NIR spectroscopy to monitor tablet manufacturing process

To monitor tableting production using near infrared (NIR) spectroscopy, chemometric models were developed to analyze peak compression force, crushing strength and content uniformity. To measure tablet content uniformity, orbifloxacin tablets with drug content ranging from 60 to 90 mg were made and analyzed using ultraviolet (UV) and NIR spectroscopy. To assess the compression force and crushing strength, several batches of tablets were made on a Stokes B2 rotary tablet press and compression force was varied from 360 to 3500 lb. Principal component analysis (PCA) was used to identify tablets with regular and capped tablets breakage patterns. Comparison of statistical parameters showed that partial least squares (PLS) models gave better fit than the multiple linear regression (MLR) models. The best fit PLS models had a standard error of calibration (SEC) and a standard error of prediction (SEP) for content uniformity of 1.13 and 1.36 mg; for compression force of 69.86 and 59.48 lb and for crushing strength 0.55 kP and 0.57 kP, respectively. NIR spectroscopy in combination with multivariate modeling is a rapid and nondestructive technique that could reliably predict content uniformity, compression force and crushing strength for orbifloxacin tablets.     

Quality by design, part III: study of curing process of sustained release coated products using NIR spectroscopy

This study investigated the potential of near infrared spectroscopy (NIRS) to assess film coat curing for tablets coated with methacrylate copolymers. The ability of NIRS to monitor film coat curing was studied and compared to conventional methods like differential scanning calorimetry (DSC) and hot-stage microscopy (HSOM). This study showed that variation in the curing temperature and duration affected the NIR spectra for all formulations. These results and the DSC and HSOM results showed that the spectral changes are due to polymer curing. In addition, glass beads, theophylline and orbifloxacin tablets were coated using Eudragit RL, RS, and L 30-D with varying ratios. Principal component analysis (PCA) was performed on the NIR spectra to investigate the effect of curing time and temperature on cast films, uncoated tablets, coated tablets and coated glass beads. Score plots showed that curing duration and temperature affected coated glass beads, uncoated and coated tablets significantly. The amount of drug released at 250 min, and the NIR spectra of cured tablets were used to develop and validate a 7-factor partial least square (PLS) regression calibration for theophylline tablets coated with Eudragit RL:RS 30-D (1:4). This study demonstrated the potential of NIRS in film coat curing and release monitoring.     

Quality by design approach of a pharmaceutical gel manufacturing process,part 1: Determination of the design space

This work was conducted in the framework of a quality by design project involving the production of a pharmaceutical gel. Preliminary work included the identification of the quality target product profiles (QTPPs) from historical values for previously manufactured batches, as well as the critical quality attributes for the process (viscosity and pH), which were used to construct a D‐optimal experimental design. The experimental design comprised 13 gel batches, three of which were replicates at the domain center intended to assess the reproducibility of the target process. The viscosity and pH models established exhibited very high linearity and negligible lack of fit (LOF). Thus, R² was 0.996 for viscosity and 0.975 for pH, and LOF was 0.53 for the former parameter and 0.84 for the latter. The process proved reproducible at the domain center. Water content and temperature were the most influential factors for viscosity, and water content and acid neutralized fraction were the most influential factors for pH. A desirability function was used to find the best compromise to optimize the QTPPs. The body of information was used to identify and define the design space for the process. A model capable of combining the two response variables into a single one was constructed to facilitate monitoring of the process. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4432–4441, 2011     

Evaluation of risk and benefit in the application of near-infrared spectroscopy to monitor the granule coating process

The purpose of this article is to study risk and benefit in the application of near-infrared (NIR) spectroscopy to the coating process of granules to monitor the process for determining the coating end point. Cylindrical granules or spherical granules were used as core granules and were coated using a fluidized bed coating apparatus by spraying coating suspension. During the coating run, samples of granules were pulled at regular intervals and amount of talc or lactose, which were the components of the film layer, were estimated by NIR spectroscopy. When the coating layer of granules was thin like the case of the spherical granules, it was possible to monitor and understand the coating process well by an application of NIR spectroscopy, because it was possible to estimate some components in the coating layer simultaneously. However, it was found that as the coating layer became thick like the case of the cylindrical granules, NIR light was scattered by titanium dioxide in the coating layer, and that the increase of the coating layer estimated from NIR spectroscopy showed the misunderstanding saturation. NIR spectroscopy could not be used for the estimation of the granule coating process even if the formulation and amount applied for the coating was same as the spherical granules. When NIR spectroscopy is intended to be used to control granule coating process, it is necessary to check the impacts of the formulation applied for coating, the amount of the coating layer, and the thickness of the coating layer on the estimations.     

Quality assessment for sustained release pharmaceutical preparations by dissolution test using microdialysis-HPLC method

Dissolution testing is a core performance test in pharmaceutical development and quality control. The conventional HPLC dissolution method (batch-sampling method) has many steps such as the filtration, collection and replenishment of sample solutions. We previously reported the dissolution test by using microdialysis methods (microdialysis-HPLC method) that can omit many steps. In this study, we investigated whether the microdialysis-HPLC method can be applied to quality assessment for sustained release preparations by a dissolution test. Calcium-channel blockers nifedipine tablets (20 mg) were used, and the test solution used was 0.2 M hydrogen phosphate-citric acid buffer (pH 6.8) with or without 1% sodium lauryl sulfate. In both test solutions, the microdialysis-HPLC method is able to accomplish continuous sampling of sample solutions, and the dissolution behaviors of original nifedipine tablets by the microdialysis-HPLC method were similar to that of the batch-sampling method. In contrast, the dissolution behaviors by the microdialysis-HPLC method were different between original nifedipine tablets and generic products, and the dissolution behaviors in the microdialysis-HPLC method tend to reflect the pharmaceutical design in comparison with the batch-sampling method. In addition, standard deviation in the microdialysis-HPLC method was lower than that of the batch-sampling method. We found that the recovery rate of nifedipine by the microdialysis-HPLC method was increased with the decrease in flow rate through dialysis probe. These findings provide significant information that can be used in pharmaceutical development and quality assessment for original and generic pharmaceutical products, which are sustained release preparations.     

Quality by design approach of a pharmaceutical gel manufacturing process,part 2: Near infrared monitoring of composition and physical parameters

We applied the principles of quality by design to the production process of a pharmaceutical gel by using the near infrared spectroscopy (NIRS) technique in combination with multivariate chemometric tools. For this purpose, we constructed a D‐optimal experimental design having normal operational condition (NOC) batches as central point. The primary aim here was to develop an expeditious NIRS method for determining the composition of a pharmaceutical gel and assess the temporal changes in major physical factors affecting the quality of the product (specifically, viscosity and pH). Gel components were quantified by using partial least squares (PLS) calibration models of the PLS1 type. The study was completed by using the batch statistical process control method to compare product batches included in the experimental design with NOC batches. Similarities and differences between the two types of batches were identified by using control charts for residuals (Q‐statistic) and Hotteling's T2 (D‐statistic). The ensuing models, which were subject to errors less than 5%, allowed the gel production process to be effectively monitored. As shown in this work, the NIRS technique is a highly suitable tool for process analytical technology. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4442–4451, 2011     

Terahertz pulsed imaging and near infrared imaging to monitor the coating process of pharmaceutical tablets

Terahertz pulsed imaging (TPI) and near infrared (NIR) imaging were used to non-destructively monitor the coating process of film-coated tablets. Samples that were taken from a pan coater at different time points were analyzed by both methods. TPI provided coating thickness maps over the whole surface of the tablets, determining the thickness of the coating at each point of the sample surface in μm, this way also giving information about the coating uniformity. The growth of the coating during the coating process was shown. NIR imaging did not provide direct thickness values, but by different absorbance values, inter- and intra-tablet differences were shown. Thus, coating thickness information was also obtained in a way that different tablets could be compared. The growth of the coating layer during the process was shown as well. Both methods provided comparable results; and they were able to detect small defects in the coating. With TPI, the whole tablet surface could be scanned; with NIR imaging information about the tablet ends at the center-band was not obtained due to the strong curvature. NIR imaging proved to be better at thinner coating layers and had a higher spatial resolution whereas TPI had the clear advantage that it provided direct thickness values.     

On-line monitoring of a granulation process by NIR spectroscopy

Near infrared (NIR) spectroscopy has been used in a noninvasively mode to develop qualitative and quantitative methods for the monitoring of a wet granulation process. The formulation contained API (10%w/w) and microcrystalline cellulose and maize starch as main excipients. NIR spectra have been acquired through the glass window of the fluidizer in reflectance mode without causing interference to neither the process nor the formulation. The spectral data has been used to develop a qualitative multivariate model based on principal component analysis (PCA). This qualitative model allows the monitoring of different steps during the granulation process only using the spectral data. Also, a quantitative calibration model based on partial least squares (PLS) methodology has been obtained to predict relevant parameters of the process, such as the moisture content, particle size distribution, and bulk density. The methodology for data acquisition, calibration modeling and method application is relatively low-cost and can be easily performed on most of the pharmaceutical sites. Based on the results, the proposed strategy provides excellent results for the monitoring of granulation processes in the pharmaceutical industry. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:336–345, 2010     

In line NIR quantification of film thickness on pharmaceutical pellets during a fluid bed coating process

Along with the risk-based approach, process analytical technology (PAT) has emerged as one of the key elements to fully implement QbD (quality-by-design). Near-infrared (NIR) spectroscopy has been extensively applied as an in-line/on-line analytical tool in biomedical and chemical industries. In this study, the film thickness on pharmaceutical pellets was examined for quantification using in-line NIR spectroscopy during a fluid-bed coating process. A precise monitoring of coating thickness and its prediction with a suitable control strategy is crucial to the quality assurance of solid dosage forms including dissolution characteristics. Pellets of a test formulation were manufactured and coated in a fluid-bed by spraying a hydroxypropyl methylcellulose (HPMC) coating solution. NIR spectra were acquired via a fiber-optic probe during the coating process, followed by multivariate analysis utilizing partial least squares (PLS) calibration models. The actual coating thickness of pellets was measured by two separate methods, confocal laser scanning microscopy (CLSM) and laser diffraction particle size analysis (LD-PSA). Both characterization methods gave superb correlation results, and all determination coefficient (R(2)) values exceeded 0.995. In addition, a prediction coating experiment for 70min demonstrated that the end-point can be accurately designated via NIR in-line monitoring with appropriate calibration models. In conclusion, our approach combining in-line NIR monitoring with CLSM and LD-PSA can be applied as an effective PAT tool for fluid-bed pellet coating processes.     

Quality by design in formulation and process development for a freeze-dried, small molecule parenteral product: a case study

A case study has been developed to illustrate one way of incorporating a Quality by Design approach into formulation and process development for a small molecule, freeze-dried parenteral product. Sodium ethacrynate was chosen as the model compound. Principal degradation products of sodium ethacrynate result from hydrolysis of the unsaturated ketone in aqueous solution, and dimer formation from a Diels-Alder condensation in the freeze-dried solid state. When the drug crystallizes in a frozen solution, the eutectic melting temperature is above -5°C. Crystallization in the frozen system is affected by pH in the range of pH 6-8 and buffer concentration in the range of 5-50 mM, where higher pH and lower buffer concentration favor crystallization. Physical state of the drug is critical to solid state stability, given the relative instability of amorphous drug. Stability was shown to vary considerably over the ranges of pH and buffer concentration examined, and vial-to-vial variability in degree of crystallinity is a potential concern. The formulation design space was constructed in terms of pH and drug concentration, and assuming a constant 5 mM concentration of buffer. The process design space is constructed to take into account limitations on the process imposed by the product and by equipment capability.     

Biodegradable PLGA microparticles for sustained release of a new GnRH antagonist: part II. In vivo performance.

Poly (DL-lactide-co-glycolide) microparticles (MP) containing a highly potent peptidic gonadotropin releasing hormone antagonist (degarelix) of interest in the prostate cancer indication were screened for biological performance. Efficacy was tested in a castrated male rat model at 3 doses (0.4, 1.0 and 1.5 mg/kg) and assessed as inhibition of luteinizing hormone (LH) secretion. When increasing the dose, onset of inhibition was faster, inhibition was more intense, and duration of action was prolonged. The MP type was also highly influent. If spray-dried and microextrusion particles exhibited comparable potencies, double emulsion microspheres were significantly less potent, both for onset and duration of inhibition. Interestingly, for the latter type it was found that the degarelix fraction released upon reconstitution in the solution for injection was significantly lower (max 0.3%), in comparison to spray-dried MP (max 2%) or microextrusion (max 4%). With the three types of particles, increasing peptide content was detrimental for duration of action, but only little difference was noticed between particles based on different polymers. At 1.5 mg/kg, LH inhibition was achieved over 36 days with spray-dried MP based on 75/25 lactate/glycolate copolymer. This was superior by 1 week to the performance of unformulated degarelix given at the same dose.     

The basis of the discovery process for a new pharmaceutical product

The basis of the discovery process for a new pharmaceutical product is in understanding the mechanism of action of a particular disease or processes in the organism related to the disease and/or its symptoms. The essence of a pharmaceutical is in the active ingredient capable of affecting processes within the organism beneficially. The discovery process includes a particular sequence of activities of various profiles of experts, about which various authors agree. The history of pharmaceutical industry (and pharmacy) is measured from one discovery of an innovative drug or approach to treatment of a particular disease to the next one. The cost of pharmaceutical products is one of the key causes of controversy related to this industry. Numerous cultures have proverbs expressing the opinion that health is priceless or that health is the greatest wealth. What if health does have a price? One of the basic premises of marketing is that price should reflect consumer value.     

Application of process analytical technology in tablet process development using NIR spectroscopy: blend uniformity, content uniformity and coating thickness measurements

Near-infrared (NIR) spectroscopy was employed as a process analytical technique in three steps of tabletting process: to monitor the blend homogeneity, evaluate the content uniformity of tablets and determine the tablets coating thickness.

A diode-array spectrometer mounted on a lab blender (SP15 NIR lab blender) was used to monitor blend uniformity using a calibration-free model with drug concentration ranging from 2.98 to 9.25% (w/w). The method developed accurately depicted the changes in concentration of the drug during blending and the positive effect of a delumping step in the production process. Blend homogeneity was reached within 2 min of the blending step post-delumping, with relative standard deviation (R.S.D.) values varying from 1.0 to 2.5% depending on the drug concentration of the blend.

A Fourier-transform spectrometer (Bruker MPA) was used to analyze content uniformity and coating thickness with calibration based models. Prediction of a validation set with tablets compacted at pressures not present in the calibration set yielded an root mean square error of cross validation (RMSEP) of 1.94%; prediction of tablets compacted at pressures present in the calibration set yielded a RMSEP of 1.48%. Performance of the model was influenced by several physical tablet properties, which could be reduced by spectral pre-processing.

A model based on reflectance spectra predicted coating thickness and its variation more accurately than the model based on transmission spectra. Inter-tablet coating variation was predicted with NIR and compared to reference thickness measurements. Both methods gave comparable results. Initial inter-tablet variation of tablets sampled in-process during coating was high, but stabilized after 30 min into the process.     

Robust calibration design in the pharmaceutical quantitative measurements with near-infrared (NIR) spectroscopy: Avoiding the chemometric pitfalls

Quantification analysis with near-infrared (NIR) spectroscopy typically requires utilizing chemometric techniques, such as partial least squares (PLS) method, to achieve the desired selectivity. This article points out a major limitation of these statistical-based calibration methods. The limitation is that the techniques suffer from the potential for chance correlation. In this article, the impact of chance correlation on the robustness of PLS model was illustrated via a pharmaceutical application with NIR to the content uniformity determination of tablets. The procedure involves evaluating the PLS models generated with two sets of calibration tablets incorporated with distinct degree of concentration correlation between the active pharmaceutical ingredient (API) and excipients. The selectivity and robustness of the two models were examined by using a series of data sets associated with placebo tablets and tablets incorporated with variations from excipient content, hardness and particle size. The result clearly revealed that the strong correlation observed in the PLS model created by the correlated design was not solely based on the API information, and there was an intrinsic difference in the variances described by the two calibration models. Diagnostic tools that enable the characterization of the chemical selectivity of the calibration model were also proposed for pharmaceutical quantitative analysis.     

The coating and the encapsulation of an interactive powder mixture and its application to sustained release preparations

Fine cohesive isoprenaline HCl particles adhered to the surface of coarser potato starch particles to form interactive mixtures. These were coated with magnesium stearate by dry mixing. To check if there was a lowering of homogeneity in the latter stage, the degree of mixing was investigated before and after adding magnesium stearate. The surface appearance of magnesium stearate-coated interactive mixtures became smoother as mixing time increased or the temperature of the powder bed during mixing was raised. Ultimately, the magnesium stearate encapsulated the particles of interactive mixture. The coated interactive mixtures improved sustained release of isoprenaline HCl over the starch mixtures alone, the effect depending on the density of the magnesium stearate. Only in encapsulated mixtures was the release rate of drug decreased as the amount of magnesium stearate increased. The release of isoprenaline HCl from the interactive mixtures followed first-order kinetics. A linear relationship existed between the first-order rate constant and the reciprocal thickness of the magnesium stearate film, indicating a diffusion-controlled system with the film having some pores.     

A novel approach to monitor coating amount by short-wavelength near-infrared spectroscopy using a tracer with a long-chain hydrocarbyl group

Investigation into the use of near-infrared (NIR) as a Process Analytical Technology has been conducted for in-process monitoring of coating amounts for oral pharmaceutical products. However, the low specificity of NIR spectra has made it time consuming and costly to establish quantitative calibration models for commercial production. Here we revealed that long-chain hydrocarbyl group compounds containing saturated hydrocarbon chains, such as cetyl and stearyl, exhibit specific and strong absorption in the short wavelength (SW)-NIR region (800–1100 nm) with limited interference from peaks corresponding to other components. To simplify the quantitative model, we used cetanol as a model tracer of coating amount to enhance detection sensitivity and analytical precision. The coating amount on crystalline cellulose granules was determined only from the intensity of NIR absorption at a single wavelength, which was attributed to the tracer. The results showed close agreement with quantitative analyses from gas chromatography and measurement of weight gain. In conclusion, we determined coating amount with considerable accuracy from NIR absorption at a single wavelength in the SW-NIR region using the long-chain hydrocarbyl containing compound as a tracer, thereby eliminating the need for complicated statistics.     

Advanced approach to build the design space for the primary drying of a pharmaceutical freeze-drying process

This paper deals with the design space of a pharmaceutical freeze-drying process. Mathematical modeling is used to investigate the effect of the operating conditions [shelf temperature (T(shelf)) and chamber pressure (P(c))] on product temperature (that has to remain below a limit value) and sublimation flux (that has to be lower than a level that would cause choked flow). The algorithm takes into account the variation of the design space with time due to the increase in the dried layer thickness. Besides T(shelf) and P(c), the dried layer thickness is used as the third coordinate of the diagram, thus resulting in just one graph that can be used to build recipes with variable operating conditions, as well as to analyze the effect of process failures. Such results are compared with those obtained when the variation of the design space with time is not accounted for; in this case, the design space comprises those operating conditions that fulfill the operation constraints throughout primary drying, thus giving a much more conservative recipe when designing the process or potentially misleading results when analyzing process failures. Finally, the proposed method has been used to design, and experimentally validate, a recipe for a pharmaceutical formulation.     

近红外技术测定布洛芬缓释胶囊的应用研究

目的：为充分发挥药品检测车快速检测的功能,根据不同的物质具有不同的近红外图谱的原理,建立布洛芬缓释胶囊的快速鉴别方法。方法：将近红外分析与高效液相分析相结合,建立这个品种的特征模型。结果：近红外分析法和实验室标准分析方法测定结果之间无显著差别,模型具有很好的稳定性。结论：近红外图谱可以对布洛芬缓释胶囊进行快速筛查,此方法快速、简便,可用于药品的现场快速分析。