Distribution Of Active Pharmaceutical Ingredient Research Articles

The influence of different acquisition settings and the focus adjustment on Raman spectral maps of pharmaceutical tablets

Pharmaceutical tablets contain a variety of active substances and excipients which could be monitored by Raman spectroscopy/microscopy. Raman microscopic spectra are affected not only by the sample composition but also by preparation/measurement conditions. The character and variability of surface morphology (of tablet slices), the appropriate levels of focusing and other adjustable settings of the measurement instrumentation represent important parameters to be considered for obtaining relevant and reliable results by Raman microscopic mapping/imaging analysis in the pharmaceutical practice. The aim of the study is to determine the effect of levels of the spotlight, and other instrumental parameters for mapping industrially manufactured pharmaceutical tablets and to find out suitable, preferably robust, parameters for routine analyses. The role of roughnesses produced by commonly used microtome slices of tablets was investigated experimentally by different focusing levels showing relatively weak (statistical) influence on data sets. The spectral quality was evaluated by signal–to–noise ratio. The data sets were processed using two multivariate statistical methods (Principal Component Analysis, Soft Independent Modeling of Class Analogy). Direct Classical Least Squares statistical modeling was optimized to show the distribution of active pharmaceutical ingredient and excipients in Raman maps. The applied different types of data evaluation confirm that the most suitable position regarding the focusing is the middle of tablet's cross-section roughness. However, we have shown that the selection of microscopic measurement modes plays a much more significant role. The selection of proper measurement mode is crucial to describe the actual sample variability and to obtain relevant data for real pharmaceutical samples. The time–consuming requirements of measurement modes need to be considered, as well, to obtain as reasonable data as possible in the given time frame in the applied pharmaceutical analysis.

Comprehensive study of the drug delivery properties of poly(l-lactide)-poly(ethylene glycol) nanoparticles in rats and tumor-bearing mice

Nanoparticles made of polylactide-poly(ethylene glycol) block-copolymer (PLA-PEG) are promising vehicles for drug delivery due to their biodegradability and controllable payload release. However, published data on the drug delivery properties of PLA-PEG nanoparticles are heterogeneous in terms of nanoparticle characteristics and mostly refer to low injected doses (a few mg nanoparticles per kg body weight). We have performed a comprehensive study of the biodistribution of nanoparticle formulations based on PLA-PEG nanoparticles of ~100nm size at injected doses of 30 to 140mg/kg body weight in healthy rats and nude tumor-bearing mice. Nanoparticle formulations differed by surface PEG coverage and by release kinetics of the encapsulated model active pharmaceutical ingredient (API).Increase in PEG coverage prolonged nanoparticle circulation half-life up to ~20h in rats and ~10h in mice and decreased retention in liver, spleen and lungs. Circulation half-life of the encapsulated API grew monotonously as the release rate slowed down. Plasma and tissue pharmacokinetics was dose-linear for inactive nanoparticles, but markedly dose-dependent for the model therapeutic formulation, presumably because of the toxic effects of released API. A mathematical model of API distribution calibrated on the data for inactive nanoparticles and conventional API form correctly predicted the distribution of the model therapeutic formulation at the lowest investigated dose, but for higher doses the toxic action of the released API had to be explicitly modelled.Our results provide a coherent illustration of the ability of controllable-release PLA-PEG nanoparticles to serve as an effective drug delivery platform to alter API biodistribution. They also underscore the importance of physiological effects of released drug in determining the biodistribution of therapeutic drug formulations at doses approaching tolerability limits.

Quantitative Evaluation of Drug Distribution in Tablets of Various Structures via Raman Mapping

Hyperspectral imaging was applied to provide quantitative spatial information about pharmaceutical samples. The aim was to characterize the distribution of active pharmaceutical ingredient (API) in manufactured samples quantitatively. Two kind of API, imipramine and spironolactone were applied in three conventional and two continuous processing technologies. The homogeneity of distributions of 10% API was determined through Raman maps applying macropixel analysis method. Non-overlapping macropixel analysis (Poole-index) and calculation of distributional homogeneity indices (DHIs) were compared as a measure of homogeneity. Non-overlapping macropixel approach proved to be more sensible than DHI evaluation. For enhancing efficacy of DHI we suggest a correction by weighting scores and considering relative standard deviations. This way the capability of DHI can be improved significantly. The very slight differences between the continuous methods (the homogeneity of which are much higher than that of conventional technologies) could be quantified.

Examining drug hydrophobicity in continuous wet granulation within a twin screw extruder

The influence of active pharmaceutical ingredient (API) hydrophobicity on continuous wet granulation was studied in twin screw granulation utilizing foamed binder delivery. The APIs examined were caffeine, acetaminophen, ibuprofen and griseofulvin and the drug load was maintained constant at 15 wt%. In order to understand the impact of these APIs on the granulation process, API and binder distribution, particle size, porosity, and fracture strength were analyzed on samples collected along the screw length. It was found that the API and binder distributions were uniform along the screws regardless of the hydrophobicity of the formulation, in contrast to literature results with liquid injection. The absence of de-mixing of the hydrophobic ingredient was hypothesized to be a result of the high spread-to-soak ratio of a foamed binder that ‘cages’ those particles within the mass of local hydrophilic solids.

Optimization of a pharmaceutical tablet formulation based on a design space approach and using vibrational spectroscopy as PAT tool

The aim of the present study was to optimize a tablet formulation using a quality by design approach. The selected methodology was based on the variation of the filler grade, taking into account the particle size distribution (PSD) of active pharmaceutical ingredient (API) in order to improve five critical quality attributes (CQAs). Thus, a mixture design of experiments (DoE) was performed at pilot scale. The blending step was monitored using near infrared (NIR) spectroscopy as process analytical technology tool enabling real-time qualitative process monitoring. Furthermore, some tablets were analyzed by Raman imaging to evaluate the API distribution within the samples. Based on the DoE results, design spaces were computed using a risk-based Bayesian predictive approach to provide for each point of the experimental domain the expected probability to get the five CQAs jointly within the specifications in the future. Finally, the optimal conditions of the identified design space were successfully validated. In conclusion, a design space approach supported by NIR and Raman spectroscopy was able to define a blend that complies with the target product profile with a quantified guarantee or risk.

Quantification of low drug concentration in model formulations with multivariate analysis using surface enhanced Raman chemical imaging

This paper reports the application of surface enhanced Raman chemical imaging (SER-CI) as a potentially non-destructive quantitative analytical method for the investigation of model pharmaceutical formulations containing the active pharmaceutical ingredient (API) in low concentrations (0.5–2%). The application of chemometric techniques for processing the spectra enables the determination of API distribution in products of different concentrations. In addition, the applied multivariate curve resolution can be proper method to identify unexpected contaminants in illicit drugs. The drastic Raman signal enhancement in the presence of silver nanoparticles provides significantly improved calibration accuracy and, at the same time, radically decreased image acquisition time compared to conventional Raman chemical imaging.

The practice and clinical implications of tablet splitting in international health

ObjectiveTablet splitting is frequently performed to facilitate correct dosing, but the practice and implications in low-income settings have rarely been discussed.MethodsWe selected eight drugs, with narrow therapeutic indices or critical dosages, frequently divided in the Lao PDR (Laos). These were split, by common techniques used in Laos, by four nurses and four laypersons. The mean percentage deviation from the theoretical expected weight and weight loss of divided tablets/capsules were recorded.ResultsFive of eight study drugs failed, on splitting, to meet European Pharmacopoeia recommendations for tablet weight deviation from the expected weight of tablet/capsule halves with 10% deviating by more than 25%. There was a significant difference in splitting accuracy between nurses and laypersons (P = 0.027). Coated and unscored tablets were less accurately split than uncoated (P = 0.03 and 0.0019 for each half) and scored (0.0001 for both halves) tablets.ConclusionThese findings have potential clinical implications on treatment outcome and the development of antimicrobial resistance. Investment by drug companies in a wider range of dosage units, particularly for narrow therapeutic index and critical dosage medicines, is strongly recommended.

A process analytical approach for quality control of dapivirine in HIV preventive vaginal rings by Raman spectroscopy

An estimated 34 million people are living with human immunodeficiency virus (HIV) worldwide. A polymeric drug delivery device for women has been developed to help reduce male to female vaginal transmission of HIV‐1. The device is an intravaginal slow‐release ring containing the antiretroviral drug dapivirine as the active pharmaceutical ingredient (API). In all pharmaceutical delivery systems, API content is a critical control point. Conventional quantification of the API in vaginal rings is a stepwise, destructive and time‐consuming process involving solvent extraction and high pressure liquid chromatography. This study investigates the potential of Raman spectroscopy for fast and non‐destructive quantification of dapivirine in intravaginal rings. Wide‐area illumination measurements were carried out on rotating rings using a custom built ring spinner. Customized reference rings of known concentrations were used to build calibration models, and the models were verified by rings from production using the established method as reference analysis. Bi‐ and multivariate calibration methods were applied. Models based on band ratios and partial least squares (PLS) regression models performed similarly well resulting in low model and prediction errors. Next to an alternative reference analysis for quality assurance, Raman can also be used as a production process performance analysis and optimization tool due to its non‐destructive nature and speed of analysis. Using measurements on connected spots over the entire ring circumference, the within ring variation in API was determined. ANOVA showed that there was a statistical difference in API distribution over the rings, information that can be of use in process optimization, for example. However, Tukey's honestly significant difference (HSD) test proved that no regions of the ring were out of specifications, indicating a stable production system. Copyright © 2014 John Wiley & Sons, Ltd.

PAT tools for the control of co-extrusion implants manufacturing process

Hot melt extrusion is a novel pharmaceutical manufacturing process technique. In this study, we identified four Critical Quality Attributes (CQAs) of the implant manufacturing process by hot melt extrusion: the implant diameter, the quantity of the Active Pharmaceutical Ingredient (API), the homogeneity distribution of API and the thickness of the membrane. We controlled the implant diameter and the quantity of API in-line with a laser measurement, NIR and Raman spectroscopy, respectively. These two different spectroscopic techniques provided comparable results. In fact, the RMSEC and RMSECV were very close in each PAT technique but NIR spectroscopy was easier to use and less sensitive to external changes. For the control of the homogeneity of API distribution and the thickness of the membrane, we used successfully Raman spectroscopy imaging. These PAT tools help reducing analysis time.

Locating Drugs Sensitively

A laser-based scanning microscopy method can map the three-dimensional distribution of active pharmaceutical ingredients (APIs) in drug tablets and powdered samples faster and with greater sensitivity than standard methods used for drug analyses, according to work reported in Analytical Chemistry (DOI: 10.1021/ac300917t). The study may lead to rapid tests for quality control and drug stability as well as for detecting counterfeits. Drug manufacturers evaluate the spatial distribution, crystallinity, and other properties that influence drug stability, bioavailability, and efficacy to ensure their uniformity in solid drug formulations. X-ray powder diffraction and Raman spectroscopy are commonly used techniques, but they suffer from various shortcomings. The X-ray method, for example, is fairly insensitive; its detection limit is often on the order of 1% for an API in a background of inactive drug formulation compounds (excipients). Imaging by Raman spectroscopy often requires long data acquisition times—se...

Analytical Characterization of an Orally-Delivered Peptide Pharmaceutical Product

The characterization of orally-delivered peptide pharmaceuticals presents several challenges to analytical methods in comparison to characterization of conventional small-molecule drugs. These challenges include the analysis and characterization of difficult-to-separate impurities, secondary structure, the amorphous solid-state form, and the integrity of enteric-coated drug delivery systems. This work presents the multidisciplinary analytical characterization of a parathyroid hormone (PTH) peptide active pharmaceutical ingredient (API) and an oral formulation of this API within enteric-coated sucrose spheres. The analysis of impurities and degradation products in API and formulated drug product was facilitated by the development of an ultrahigh-performance liquid chromatography (UHPLC) method for analysis by high-resolution mass spectrometry (MS). The use of UHPLC allowed for additional resolution needed to detect impurities and degradation products of interest. The secondary structure was probed using a combination of solution-state NMR, infrared, and circular dichroism spectroscopic methods. Solid-state NMR is used to detect amorphous API in a nondestructive manner directly within the coated sucrose sphere formulation. Fluorescence and Raman microscopy were used in conjunction with Raman mapping to show enteric coating integrity and observe the distribution of API beneath the enteric-coating on the sucrose spheres. The methods are combined in a multidisciplinary approach to characterize the quality of the enteric-coated peptide product.

Microfluidic chip‐based liquid chromatography coupled to mass spectrometry for determination of small molecules in bioanalytical applications

The development and integration of microfabricated liquid chromatography (LC) microchips have increased dramatically in the last decade due to the needs of enhanced sensitivity and rapid analysis as well as the rising concern on reducing environmental impacts of chemicals used in various types of chemical and biochemical analyses. Recent development of microfluidic chip-based LC mass spectrometry (chip-based LC-MS) has played an important role in proteomic research for high throughput analysis. To date, the use of chip-based LC-MS for determination of small molecules, such as biomarkers, active pharmaceutical ingredients (APIs), and drugs of abuse and their metabolites, in clinical and pharmaceutical applications has not been thoroughly investigated. This mini-review summarizes the utilization of commercial chip-based LC-MS systems for determination of small molecules in bioanalytical applications, including drug metabolites and disease/tumor-associated biomarkers in clinical samples as well as adsorption, distribution, metabolism, and excretion studies of APIs in drug discovery and development. The different types of commercial chip-based interfaces for LC-MS analysis are discussed first and followed by applications of chip-based LC-MS on biological samples as well as the comparison with other LC-MS techniques.

Pharmaceutical evaluation of steroidal ointments by ATR-IR chemical imaging: Distribution of active and inactive pharmaceutical ingredients

We recently used micro attenuated total reflection infrared (ATR-IR) spectroscopy to conduct imaging analysis of ointments and evaluate the distributions of the active pharmaceutical ingredient (API) and excipients. An alclometasone dipropionate (ALC) ointment was used as a model product. Almeta®, a brand-name product, had a domain with absorbance at 1656cm−1 attributable to the carbonyl group of ALC, the API. Absorbances at 1040 and 3300cm−1 were also noted in this domain, indicating the presence of the solubilizer, propylene glycol. Data also suggested the presence of benzyl alcohol in this domain. More detailed analysis showed the distribution of surfactants and other excipients in the base. Similar results were obtained for Vitra®, a generic version of Almeta®. Imaging analysis with micro ATR-IR confirmed that both ointments are liquid droplet dispersions with ALC dissolved in propylene glycol and dispersed in a base. However, minor differences in the ingredient distributions of the two ointments were detected and reflect differences in excipient concentrations and type, or manufacturing differences. In summary, we used micro ATR-IR for imaging analysis of an original ointment, Almeta®, and its generic form Vitra®, and established a method for visually evaluating the distributions of the API and excipients in these ointments.

Applications of cathodoluminescence spectroscopy and imaging in the characterisation of pharmaceutical materials

Cathodoluminescence (CL) analysis is a mature technique which utilises the light that is emitted from materials when they are bombarded with a beam of high energy electrons to produce spectra and spectral images of specimens. This technique is used routinely in many industries as a non-destructive way to investigate and characterise inorganic compounds, such as minerals, ceramics and semiconductors, as they are being examined in a scanning electron microscope, but is seldom used to study organic compounds. The discovery that many (up to about 80%) active pharmaceutical ingredients (APIs) and API-like compounds are cathodoluminescent has resulted in the development of CL analysis as a novel technique to rapidly visualise the solid state spatial distribution of APIs in drug products as they are being examined by scanning electron microscopy. Spectral images of API particles dispersed in drug products (a tablet, a multiparticulate bead, and a dry powder inhalation blend) were acquired to illustrate the practical application of CL imaging to support product development or to optimise manufacturing processes. This study has also revealed that CL spectroscopy can distinguish between crystalline and amorphous materials and is sensitive the differences between the solid forms of some organic compounds, such as salts and polymorphs. Up to 80% of commonly used excipients are non-cathodoluminescent and this has the advantage of enabling APIs in formulated products to be imaged without interference. As part of the investigation to explore the use of CL as a way to identify polymorphs and monitor phase transformations, it was discovered that by recrystallising fused carbamazepine, the metastable Form IV was unexpectedly produced.

Near infrared and Raman spectroscopy as Process Analytical Technology tools for the manufacturing of silicone-based drug reservoirs

Using near infrared (NIR) and Raman spectroscopy as PAT tools, 3 critical quality attributes of a silicone-based drug reservoir were studied. First, the Active Pharmaceutical Ingredient (API) homogeneity in the reservoir was evaluated using Raman spectroscopy (mapping): the API distribution within the industrial drug reservoirs was found to be homogeneous while API aggregates were detected in laboratory scale samples manufactured with a non optimal mixing process. Second, the crosslinking process of the reservoirs was monitored at different temperatures with NIR spectroscopy. Conformity tests and Principal Component Analysis (PCA) were performed on the collected data to find out the relation between the temperature and the time necessary to reach the crosslinking endpoints. An agreement was found between the conformity test results and the PCA results. Compared to the conformity test method, PCA had the advantage to discriminate the heating effect from the crosslinking effect occurring together during the monitored process. Therefore the 2 approaches were found to be complementary. Third, based on the HPLC reference method, a NIR model able to quantify the API in the drug reservoir was developed and thoroughly validated. Partial Least Squares (PLS) regression on the calibration set was performed to build prediction models of which the ability to quantify accurately was tested with the external validation set. The 1.2% Root Mean Squared Error of Prediction (RMSEP) of the NIR model indicated the global accuracy of the model. The accuracy profile based on tolerance intervals was used to generate a complete validation report. The 95% tolerance interval calculated on the validation results indicated that each future result will have a relative error below ±5% with a probability of at least 95%. In conclusion, 3 critical quality attributes of silicone-based drug reservoirs were quickly and efficiently evaluated by NIR and Raman spectroscopy.

Fast assessment of the surface distribution of API and excipients in tablets using NIR-hyperspectral imaging

The inclusion of hyperspectral imaging systems in the manufacturing and development of pharmaceutical products is allowing a successful improvement in the quality control of solid dosage forms. The correct distribution not only of active pharmaceutical ingredient (API) but also of the rest of excipients is essential to assure the correct behavior of the tablet when ingested. This is especially relevant in tablets with low content of potent APIs, in which the prescribed intake dosage frequently corresponds to half-a-tablet. Therefore, the aim of this work is to study the surface distribution of the compounds in tablets with low API content. The proposed procedure includes the scanning of the tablet surface using near infrared hyperspectral spectroscopy in association with multivariate curve resolution (MCR) techniques to obtain selective pictures for each individual compound and to allow the fast assessment of their distribution in the measured surface. As an example, a set of commercial Lorazepam tablets (approximately 1% mass fraction of API, and four excipients) were analyzed. The results obtained show the capacity of the proposed methodology as an expedite approach to evaluate the uniformity of the contents between and within tablets. A method to estimate the homogeneity distribution of API in the two halves of the tablet is also proposed.

Raman mapping of pharmaceuticals

Raman spectroscopy may be implemented through a microscope to provide fine scale axial and lateral chemical maps. The molecular structure of many drugs makes Raman spectroscopy particularly well suited to the investigation of pharmaceutical systems. Chemometric methods currently used to assess bulk Raman spectroscopic data are typically applied to Raman mapping data from pharmaceuticals; few reports exist where the spatial information inherent to a mapped dataset is used for the calculation of chemical maps. Both univariate and multivariate methods have been applied to Raman mapping data to determine the distribution of active pharmaceutical ingredients (APIs) in tablets, solid dispersions for increased solubility and controlled release devices. The ability to axially (depth) profile using Raman mapping has been used in studies of API penetration through membranes, cellular uptake of drug delivery liposomes, and initial API distribution and subsequent elution from coatings of medical devices. New instrumental developments will increase the efficiency of Raman mapping and lead to greater utilisation of Raman mapping for analyses of pharmaceutical systems.

Near InfraRed Spectroscopy homogeneity evaluation of complex powder blends in a small-scale pharmaceutical preformulation process, a real-life application

Near InfraRed Spectroscopy (NIRS) is a potentially powerful tool for assessing the homogeneity of industrial powder blends. In the particular context of hospital manufacturing, we considered the introduction of the technique at a small pharmaceutical process scale, with the objective of following blend homogeneity in mixtures of seven components. This article investigates the performance of various NIRS-based methodologies to assess powder blending. The formulation studied is prescribed in haematology unit, as part of the treatment for digestive decontamination in children receiving stem-cell transplantation. It is composed of the active pharmaceutical ingredients (APIs) colimycin and tobramycin and five excipients. We evaluated 39 different blends composing 14 different formulations, with uncorrelated proportions of constituents between these 14 formulations. The reference methods used to establish the NIRS models were gravimetry and a High Performance Liquid Chromatography method coupled to an Evaporative Light Scattering Detection. Unsupervised and supervised qualitative and quantitative chemometric methods were performed to assess powder blend homogeneity using a bench top instrument equipped with an optical fibre. For qualitative evaluations, unsupervised Moving Block Standard Deviation, autocorrelation functions and Partial Least Square Discriminant Analysis (PLS-DA) were used. For quantitative evaluations, Partial Least Square Cross-Validated models were chosen. Results are expressed as API, and major excipient percentages of theoretical values as a function of blending time. The 14 different formulations were only satisfactorily discriminated by supervised algorithms, such as an optimised PLS-DA model. The homogeneity state was demonstrated after 16 min of blending, quantifying three components with a precision between 1.2% and 1.4% w/w. This study demonstrates, for the first time, the effective implementation of NIRS for blend homogeneity evaluation, as early as the preformulation step in a small hospital manufacturing unit. It shows how NIRS involving sampling with an optic fibre can be useful to characterise, optimise and control a small-scale mixing processes on the basis of the distribution of APIs and excipients during blending.