Selecting Counterions to Improve Ionized Hydrophilic Drug Encapsulation in Polymeric Nanoparticles.

Hydrophobic ion pairing (HIP) can successfully increase the drug loading and control the release kinetics of ionizable hydrophilic drugs, addressing challenges that prevent these molecules from reaching the clinic. Nevertheless, polymeric nanoparticle (PNP) formulation development requires trial-and-error experimentation to meet the target product profile, which is laborious and costly. Herein, we design a preformulation framework (solid-state screening, computational approach, and solubility in PNP-forming emulsion) to understand counterion-drug-polymer interactions and accelerate the PNP formulation development for HIP systems. The HIP interactions between a small hydrophilic molecule, AZD2811, and counterions with different molecular structures were investigated. Cyclic counterions formed amorphous ion pairs with AZD2811; the 0.7 pamoic acid/1.0 AZD2811 complex had the highest glass transition temperature (Tg; 162 °C) and the greatest drug loading (22%) and remained as phase-separated amorphous nanosized domains inside the polymer matrix. Palmitic acid (linear counterion) showed negligible interactions with AZD2811 (crystalline-free drug/counterion forms), leading to a significantly lower drug loading despite having similar log P and pKa with pamoic acid. Computational calculations illustrated that cyclic counterions interact more strongly with AZD2811 than linear counterions through dispersive interactions (offset π-π interactions). Solubility data indicated that the pamoic acid/AZD2811 complex has a lower organic phase solubility than AZD2811-free base; hence, it may be expected to precipitate more rapidly in the nanodroplets, thus increasing drug loading. Our work provides a generalizable preformulation framework, complementing traditional performance-indicating parameters, to identify optimal counterions rapidly and accelerate the development of hydrophilic drug PNP formulations while achieving high drug loading without laborious trial-and-error experimentation.

Terahertz frequency-domain sensing combined with quantitative multivariate analysis for pharmaceutical tablet inspection.

Near infrared (NIR) and Raman spectroscopy combined with multivariate analysis are established techniques for the identification and quantification of chemical properties of pharmaceutical tablets like the concentration of active pharmaceutical ingredients (API). However, these techniques suffer from a high sensitivity to particle size variations and are not ideal for the characterization of physical properties of tablets such as tablet density. In this work, we have explored the feasibility of terahertz frequency-domain spectroscopy, with the advantage of low scattering effects, combined with multivariate analysis to quantify API concentration and tablet density. We studied 33 tablets, consisting of Ibuprofen, Mannitol, and a lubricant with API concentration and filler particle size as the design factors. The terahertz signal was measured in transmission mode across the frequency range 750 GHz to 1.5 THz using a vector network analyzer, frequency extenders, horn antennas, and four off-axis parabolic mirrors. The attenuation spectral data were pre-processed and orthogonal partial least square (OPLS) regression was applied to the spectral data to obtain quantitative prediction models for API concentration and tablet density. The performance of the models was assessed using test sets. While a fair model was obtained for API concentration, a high-quality model was demonstrated for tablet density. The coefficient of determination (R2) for the calibration set was 0.97 for tablet density and 0.98 for API concentration, while the relative prediction errors for the test set were 0.7% and 6% for tablet density and API concentration models, respectively. In conclusion, terahertz spectroscopy demonstrated to be a complementary technique to Raman and NIR spectroscopy, which enables the characterization of physical properties of tablets like tablet density, and the characterization of API concentration with the advantage of low scattering effects.

Terahertz frequency domain sensing for fast porosity measurement of pharmaceutical tablets.

Porosity is an important property of pharmaceutical tablets since it may affect tablet disintegration, dissolution, and bio-availability. It is, therefore, essential to establish non-destructive, fast, and compact techniques to assess porosity, in situ, during the manufacturing process. In this paper, the terahertz frequency-domain (THz-FD) technique was explored as a fast, non-destructive, and sensitive technique for porosity measurement of pharmaceutical tablets. We studied a sample set of 69 tablets with different design factors, such as particle size of the active pharmaceutical ingredient (API), Ibuprofen, particle size of the filler, Mannitol, API concentration, and compaction force. The signal transmitted through each tablet was measured across the frequency range 500-750 GHz using a vector network analyzer combined with a quasi-optical set-up consisting of four off-axis parabolic mirrors to guide and focus the beam. We first extracted the effective refractive index of each tablet from the measured complex transmission coefficients and then translated it to porosity, using an empirical linear relation between effective refractive index and tablet density. The results show that the THz-FD technique was highly sensitive to the variations of the design factors, showing that filler particle size and compaction force had a significant impact on the effective refractive index of the tablets and, consequently, porosity. Moreover, the fragmentation behaviour of particles was observed by THz porosity measurements and was verified with scanning electron microscopy of the cross-section of tablets. In conclusion, the THz-FD technique, based on electronic solutions, allows for fast, sensitive, and non-destructive porosity measurement that opens for compact instrument systems capable of in situ sensing in tablet manufacturing.

Optical porosimetry by gas in scattering media absorption spectroscopy (GASMAS) applied to roller compaction ribbons.

Currently, there is a need for new technology for in-line or fast at-line assessment of solid material porosity. One specific gap is a fast technology to be used in connection to roller compaction (RC) manufacturing, where the porosity of the RC ribbons is critical to the manufacturing of tablets of the right tensile strength and disintegration properties. In this paper, the development of an at-line technology for fast, non-destructive assessment of porosity of RC ribbons is reported. The technology is based on a diode laser spectroscopic technique called Gas in scattering media absorption spectroscopy (GASMAS). GASMAS measures the sample voids by laser light, giving the distance through air. The total distance the light travels is measured using time-of-flight spectroscopy (TOFS). The ratio of these measures gives an "optical porosity", which through theory relates to the porosity of the sample. We present a description of the technology, evaluations of measurement robustness and results from an experimental design where roller compactor, roll force, roll gap and formulation were varied. It is concluded that the data from two different pharmaceutical formulations is supported by the same calibration curve, which indicates that optical porosimetry is a general technique for pharmaceutical materials that does not require frequent calibrations.

Comparison between integrated continuous direct compression line and batch processing - The effect of raw material properties.

There is a current trend in pharmaceutical manufacturing to shift from traditional batch manufacture to continuous manufacturing. The purpose of this study was to test the ability of an integrated continuous direct compression (CDC) line, in relation to batch processing, to achieve consistent tablet quality over long processing periods for formulations with poor flow properties or with a tendency to segregate. The study design included four industrially relevant formulations with different segregation indices and flow properties induced through different grades of the Active Pharmaceutical Ingredient (API), paracetamol, and major filler as well as varying the amount of API. The performance metrics investigated were content, uniformity of content, tablet weight, and tablet strength. The overall process stability over time was significantly improved with the CDC line as compared to the batch process. For all the formulations with a high API content, the CDC line provided better or equal uniformity of content and tablet weight as compared to batch. The CDC line was especially efficient in providing a stable content and tablet weight for poorly flowing formulations containing the standard, cohesive, grade of API. The only formulation that performed better in the batch process was the formulation with a low API content. Thus, for this formulation, the batch process achieved lower variation in tablet content since maintaining a low feed rate for the API proved challenging in the CDC line. In addition, some of the API became stuck in the CDC line between feeding and tableting, most likely at the funnel in the mixer inlet, highlighting the need for properly designed interfaces between units. The insensitivity of the CDC line towards poor flow indicates that one could use direct compression at high drug load compositions of poorly flowing powder blends that could not be processed via batch manufacturing.

Designing flexible low-viscous sieving media for capillary electrophoresis analysis of ribonucleic acids.

Modified messenger RNA (mRNA) has recently become a new prospective class of drug product. Consequently, stability indicating separation methods are needed to progress pharmaceutical development of mRNA. A promising separation technique for the analysis of mRNA is capillary gel electrophoresis (CGE). We designed a flexible, low-viscous sieving medium for CGE, based on high mass linear polyvinylpyrrolidone (PVP) and glycerol. A Central Composite Face-centered design resulted in a strong model that allowed us to predict suitable sieving media compositions by using multi-objective optimization. The way of working proposed in this paper gives analysts the freedom to design a suitable sieving medium for their response(s) of interest, for purity and stability analysis of polynucleotides with a size around 100-1000 bases. Depending on the criteria for the analysis there will be a trade-off between different suitable conditions. By using this method, we created a sieving medium that was able to improve resolution, peak height and analysis time of an RNA ladder compared to the current commercially available separation gels.

Matrix Effects in Quantitative Assessment of Pharmaceutical Tablets Using Transmission Raman and Near-Infrared (NIR) Spectroscopy.

Raman spectroscopy can be an alternative to near-infrared spectroscopy (NIR) for nondestructive quantitative analysis of solid pharmaceutical formulations. Compared with NIR spectra, Raman spectra have much better selectivity, but subsampling was always an issue for quantitative assessment. Raman spectroscopy in transmission mode has reduced this issue, since a large volume of the sample is measured in transmission mode. The sample matrix, such as particle size of the drug substance in a tablet, may affect the Raman signal. In this work, matrix effects in transmission NIR and Raman spectroscopy were systematically investigated for a solid pharmaceutical formulation. Tablets were manufactured according to an experimental design, varying the factors particle size of the drug substance (DS), particle size of the filler, compression force, and content of drug substance. All factors were varied at two levels plus a center point, except the drug substance content, which was varied at five levels. Six tablets from each experimental point were measured with transmission NIR and Raman spectroscopy, and their concentration of DS was determined for a third of those tablets. Principal component analysis of NIR and Raman spectra showed that the drug substance content and particle size, the particle size of the filler, and the compression force affected both NIR and Raman spectra. For quantitative assessment, orthogonal partial least squares regression was applied. All factors varied in the experimental design influenced the prediction of the DS content to some extent, both for NIR and Raman spectroscopy, the particle size of the filler having the largest effect. When all matrix variations were included in the multivariate calibrations, however, good predictions of all types of tablets were obtained, both for NIR and Raman spectroscopy. The prediction error using transmission Raman spectroscopy was about 30% lower than that obtained with transmission NIR spectroscopy.

Transmission near-infrared (NIR) and photon time-of-flight (PTOF) spectroscopy in a comparative analysis of pharmaceuticals.

We present a comprehensive study of the application of photon time-of-flight spectroscopy (PTOFS) in the wavelength range 1050-1350 nm as a spectroscopic technique for the evaluation of the chemical composition and structural properties of pharmaceutical tablets. PTOFS is compared to transmission near-infrared spectroscopy (NIRS). In contrast to transmission NIRS, PTOFS is capable of directly and independently determining the absorption and reduced scattering coefficients of the medium. Chemometric models were built on the evaluated absorption spectra for predicting tablet drug concentration. Results are compared to corresponding predictions built on transmission NIRS measurements. The predictive ability of PTOFS and transmission NIRS is comparable when models are based on uniformly distributed tablet sets. For non-uniform distribution of tablets based on particle sizes, the prediction ability of PTOFS is better than that of transmission NIRS. Analysis of reduced scattering spectra shows that PTOFS is able to characterize tablet microstructure and manufacturing process parameters. In contrast to the chemometric pseudo-variables provided by transmission NIRS, PTOFS provides physically meaningful quantities such as scattering strength and slope of particle size. The ability of PTOFS to quantify the reduced scattering spectra, together with its robustness in predicting drug content, makes it suitable for such evaluations in the pharmaceutical industry.

Broadband photon time-of-flight spectroscopy of pharmaceuticals and highly scattering plastics in the VIS and close NIR spectral ranges.

We present extended spectroscopic analysis of pharmaceutical tablets in the close near infrared spectral range performed using broadband photon time-of-flight (PTOF) absorption and scattering spectra measurements. We show that the absorption spectra can be used to perform evaluation of the chemical composition of pharmaceutical tablets without need for chemo-metric calibration. The spectroscopic analysis was performed using an advanced PTOF spectrometer operating in the 650 to 1400 nm spectral range. By employing temporal stabilization of the system we achieve the high precision of 0.5% required to evaluate the concentration of tablet ingredients. In order to further illustrate the performance of the system, we present the first ever reported broadband evaluation of absorption and scattering spectra from pure and doped Spectralon®.

Combining experimental design and orthogonal projections to latent structures to study the influence of microcrystalline cellulose properties on roll compaction.

Roll compaction is gaining importance in pharmaceutical industry for the dry granulation of heat or moisture sensitive powder blends with poor flowing properties prior to tabletting. We studied the influence of microcrystalline cellulose (MCC) properties on the roll compaction process and the consecutive steps in tablet manufacturing. Four dissimilar MCC grades, selected by subjecting their physical characteristics to principal components analysis, and three speed ratios, i.e. the ratio of the feed screw speed and the roll speed of the roll compactor, were included in a full factorial design. Orthogonal projection to latent structures was then used to model the properties of the resulting roll compacted products (ribbons, granules and tablets) as a function of the physical MCC properties and the speed ratio. This modified version of partial least squares regression separates variation in the design correlated to the considered response from the variation orthogonal to that response. The contributions of the MCC properties and the speed ratio to the predictive and orthogonal components of the models were used to evaluate the effect of the design variation. The models indicated that several MCC properties, e.g. bulk density and compressibility, affected all granule and tablet properties, but only one studied ribbon property: porosity. After roll compaction, Ceolus KG 1000 resulted in tablets with obvious higher tensile strength and lower disintegration time compared to the other MCC grades. This study confirmed that the particle size increase caused by roll compaction is highly responsible for the tensile strength decrease of the tablets.

Quantitative transmission Raman spectroscopy of pharmaceutical tablets and capsules.

Quantitative analysis of pharmaceutical formulations using the new approach of transmission Raman spectroscopy has been investigated. For comparison, measurements were also made in conventional backscatter mode. The experimental setup consisted of a Raman probe-based spectrometer with 785 nm excitation for measurements in backscatter mode. In transmission mode the same system was used to detect the Raman scattered light, while an external diode laser of the same type was used as excitation source. Quantitative partial least squares models were developed for both measurement modes. The results for tablets show that the prediction error for an independent test set was lower for the transmission measurements with a relative root mean square error of about 2.2% as compared with 2.9% for the backscatter mode. Furthermore, the models were simpler in the transmission case, for which only a single partial least squares (PLS) component was required to explain the variation. The main reason for the improvement using the transmission mode is a more representative sampling of the tablets compared with the backscatter mode. Capsules containing mixtures of pharmaceutical powders were also assessed by transmission only. The quantitative results for the capsules' contents were good, with a prediction error of 3.6% w/w for an independent test set. The advantage of transmission Raman over backscatter Raman spectroscopy has been demonstrated for quantitative analysis of pharmaceutical formulations, and the prospects for reliable, lean calibrations for pharmaceutical analysis is discussed.

Applying spectral peak area analysis in near-infrared spectroscopy moisture assays.

Spectral peak area analysis has in this study been shown to be a viable method in near-infrared spectroscopy (NIRS) moisture assays. The study also shows that the required number of calibration samples can be minimized, and the method is, therefore, especially suitable for moisture assays in early formulation development and in-situ process monitoring. Diffuse NIRS was utilized in the development of moisture assays for the model compounds polyvinylpyrrolidone and hydroxypropyl-beta-cyclodextrin and also for a lyophilized formulation. Reference data were obtained using coulometric Karl Fischer titration. The NIRS measurements were performed through the bottoms of the sample vials using either a Fourier Transform-Near-Infrared (FT-NIR) spectrometer fitted with a diffuse reflectance probe or a dispersive single beam spectrometer. The ratios of the peak areas of a water peak at 5200 cm(-1) and a reference peak were evaluated using linear regression analysis. The spectral peak area analysis method was compared with a conventional partial least squares regression method. The moisture assays were verified using independent test sets. The investigated moisture range was 0-22% for the samples of PVP, 0-8.5% for the samples of hydroxypropyl-beta-cyclodextrin and 0.5-8.5% for the samples of the lyophilized formulation. The results of the spectral peak area analysis and the conventional partial least squares regression were similar, but the peak area method was more robust and could also make accurate predictions for lyophilized PVP samples, although the calibration set consisted of non-lyophilized samples. The peak area method required fewer calibration samples than the conventional partial least squares regression method.

Transfer of NIR calibrations for pharmaceutical formulations between different instruments.

In order to evaluate how well existing techniques for transferring NIR calibrations perform for solid pharmaceutical formulations, a study on four assays of active ingredients was undertaken. The study included two configurations of dispersive NIR instruments and one Fourier transform (FT) instrument. Three methods for calibration transfer: slope/bias correction, local centring and piecewise direct standardisation (PDS), were tested and evaluated. Our conclusions are that the calibration transfer methods tested can perform equally well. It was shown that it is possible to transfer calibrations between instruments of different configurations or even of different types, without loosing the prediction ability of the calibration. To achieve a good calibration transfer, a larger variation in the content of the active ingredient in the samples and more samples are needed for the slope and bias correction method compared to the local centring method. For PDS to be a successful calibration transfer method, an optimisation of the number of transfer samples and how they are selected together with various factors specific for this method is needed. Local centring is the preferred transfer method as its performance is excellent yet it is simple to perform, no optimisation is needed, only a few transfer samples are required and the transfer samples do not have to vary in their content of the active ingredient.

Evaluation of basic algorithms for transferring quantitative multivariate calibrations between scanning grating and FT NIR spectrometers.

A key issue in near infrared spectroscopy (NIR) is the possibility to use calibrations generated on one instrument for predictions on others. A number of methods for calibration transfer have been proposed, but which method to choose is typically not straightforward. An evaluation of a number of methods for transferring quantitative calibrations between different instruments was carried out on near infrared diffuse-reflectance data from a pharmaceutical formulation. Six instruments were included in the study, five of which were scanning grating instruments, both with and without fibre-optic probe configuration, and one of which was a Fourier-transform instrument, equipped with a fibre-optic probe. The results show that it is possible to transfer calibrations between different instruments, provided that a structured procedure is used. Simple techniques for calibration transfer, such as slope/bias correction on the predicted results, as well as standard normal variate transformation and local centring of the raw spectra, gave considerably lower prediction errors on transfer than did standardisation with a certified diffuse-reflectance standard, or direct transfer without any transfer function. Notably, including more than one instrument in the calibration also improved the prediction ability of the models on calibration transfer. No significant differences in wavelength scale were found when a certified diffuse-reflectance wavelength standard was measured on the instruments studied. Nor did simulated wavelength scale differences below +/-0.3 nm cause any significant change in the prediction errors.

In-situ near-infrared spectroscopy monitoring of the lyophilization process.

PURPOSE: The purpose of this work was to demonstrate the feasibility of using near-infrared spectroscopy (NIRS) to monitor the freeze-drying process in-situ. METHODS: The experiment was performed in a pilot-scale freeze-dryer, in which the NIRS probe was interfaced using a lead-through to the lyophilizer. Special equipment for the sample presentation was developed. NIRS measurements were made using a FT (Fourier transform)-NIR spectrometer fitted with a single fiber reflectance probe. RESULTS: The physical changes, that is, freezing, sublimation, and desorption, generated significant spectral changes. There was good agreement between NIRS monitoring and product temperature monitoring about the freezing process and the transition from frozen solution to ice-free material. The NIRS monitoring also provided new information about the process that was not possible to detect with product temperature monitoring, such as the rate of the desorption process and the steady-state where the drying was complete. The NIRS monitoring yields significantly more information about the actual process and essentially explains the observed changes of the product temperature during the lyophilization process. CONCLUSIONS: NIRS monitoring is a viable tool for in-situ monitoring, both qualitatively and quantitatively. It can facilitate investigations of the drying process within a sample. The small volume monitored makes sample presentation very important.