Measuring The Bipolar Charge Distributions of Fine Particle Aerosol Clouds of Commercial PMDI Suspensions Using a Bipolar Next Generation Impactor (bp-NGI).

PURPOSE: To measure the charge to mass (Q/M) ratios of the impactor stage masses (ISM) from commercial Flixotide™ 250 µg Evohaler, containing fluticasone propionate (FP), Serevent™ 25 µg Evohaler, containing salmeterol xinafoate (SX), and a combination Seretide™ 250/25 µg (FP/SX) Evohaler metered dose inhalers (MDIs). Measurements were performed with a purpose built bipolar charge measurement apparatus (bp-NGI) based on an electrostatic precipitator, which was directly connected below Stage 2 of a Next Generation Impactor (NGI). METHODS: Five successive shots of the respective MDIs were actuated through the bp-NGI. The whole ISM doses were electrostatically precipitated to determine their negative, positive and net Q/m ratios. RESULTS: The ISM doses collected in the bp-NGI were shown to be equivalent to those collected in a standard NGI. FP particles, actuated from Flixotide™ and Seretide™ MDIs, exhibited greater quantities of negatively charged particles than positive. However, the Q/m ratios of the positively charged particles were greater in magnitude. SX particles from Serevent™ exhibited a greater quantity of positively charged particles whereas SX aerosol particles from Seretide™ exhibited a greater quantity of negatively charged particles. The Q/m ratio of the negatively charged SX particles in Serevent™ was greater in magnitude than the positively charged particles. CONCLUSIONS: The bp-NGI was used to quantify the bipolar Q/m ratios of aerosol particles collected from the ISMs of commercial MDI products. The positive charge recorded for each of the three MDIs may have been enhanced by the presence of charged ice crystals formed from the propellant during the aerosolisation process.

Mechanistic modeling of twin screw wet granulation for pharmaceutical formulations: Calibration, sensitivity analysis, and model-driven workflow.

Wet granulation, a particle size enlargement process, can significantly enhance the critical quality attributes of powders and improve the ability to form tablets in pharmaceutical manufacturing. In this study, a mechanistic-based population balance model is applied to twin screw wet granulation. This model incorporated a recently developed breakage kernel specifically designed for twin screw granulation, along with nucleation, layering, and consolidation. Calibration and validation were performed on Hydrochlorothiazide and Acetaminophen formulations, which exhibit different particle size and wettability characteristics. Utilizing a compartmental experimental dataset, a comprehensive global sensitivity analysis identified critical inputs impacting quality attributes. The study revealed that the nucleation rate process model, effectively represented particle size distributions for both formulations. Adjustments to nucleation and breakage rate parameters, influenced by material properties and screw configuration, improved the model's accuracy. A model-driven workflow was proposed, offering step-by-step guidelines and facilitating PBM model usage, providing essential details for future active pharmaceutical ingredient (API) formulations.

Releasing fast and slow: Non-destructive prediction of density and drug release from SLS 3D printed tablets using NIR spectroscopy.

Selective laser sintering (SLS) 3D printing is a revolutionary 3D printing technology that has been found capable of creating drug products with varied release profiles by changing the laser scanning speed. Here, SLS 3D printed formulations (printlets) loaded with a narrow therapeutic index drug (theophylline) were produced using SLS 3D printing at varying laser scanning speeds (100-180 mm/s). The use of reflectance Fourier Transform - Near Infrared (FT-NIR) spectroscopy was evaluated as a non-destructive approach to predicting 3D printed tablet density and drug release at 2 h and 4 h. The printed drug products formulated with a higher laser speed exhibited an accelerated drug release and reduced density compared with the slower laser scanning speeds. Univariate calibration models were developed based on a baseline shift in the spectra in the third overtone region upon changing physical properties. For density prediction, the developed univariate model had high linearity (R2 value = 0.9335) and accuracy (error < 0.029 mg/mm3). For drug release prediction at 2 h and 4 h, the developed univariate models demonstrated a linear correlation (R2 values of 0.9383 and 0.9167, respectively) and accuracy (error < 4.4%). The predicted vs. actual dissolution profiles were found to be statistically similar (f2 > 50) for all of the test printlets. Overall, this article demonstrates the feasibility of SLS 3D printing to produce drug products containing a narrow therapeutic index drug across a range of drug release profiles, as well as the potential for FT-NIR spectroscopy to predict the physical characteristics of SLS 3D printed drug products (drug release and density) as a non-destructive quality control method at the point-of-care.

T-shaped partial least squares for high-dosed new active pharmaceutical ingredients in continuous twin-screw wet granulation: Granule size prediction with limited material information.

This work presents a granule size prediction approach applicable to diverse formulations containing new active pharmaceutical ingredients (APIs) in continuous twin-screw wet granulation. The approach consists of a surrogate selection method to identify similar materials with new APIs and a T-shaped partial least squares (T-PLS) model for granule size prediction across varying formulations and process conditions. We devised a surrogate material selection method, employing a combination of linear pre-processing and nonlinear classification algorithms, which effectively identified suitable surrogates for new materials. Using only material properties obtained through four characterization methods, our approach demonstrated its predictive prowess. The selected surrogate methods were seamlessly integrated with our developed T-PLS model, which was meticulously validated for high-dose formulations involving three new APIs. When surrogating new APIs based on Gaussian process classification, we achieved the lowest prediction errors, signifying the method's robustness. The predicted d-values were within the range of uncertainty bounds for all cases, except for d90 of API C. Notably, the approach offers a direct and efficient solution for early-phase formulation and process development, considerably reducing the need for extensive experimental work. By relying on just four material characterization methods, it streamlines the research process while maintaining a high degree of accuracy.

Prediction of Solid-State Form of SLS 3D Printed Medicines Using NIR and Raman Spectroscopy.

Selective laser sintering (SLS) 3D printing is capable of revolutionising pharmaceutical manufacturing, by producing amorphous solid dispersions in a one-step manufacturing process. Here, 3D-printed formulations loaded with a model BCS class II drug (20% w/w itraconazole) and three grades of hydroxypropyl cellulose (HPC) polymer (-SSL, -SL and -L) were produced using SLS 3D printing. Interestingly, the polymers with higher molecular weights (HPC-L and -SL) were found to undergo a uniform sintering process, attributed to the better powder flow characteristics, compared with the lower molecular weight grade (HPC-SSL). XRPD analyses found that the SLS 3D printing process resulted in amorphous conversion of itraconazole for all three polymers, with HPC-SSL retaining a small amount of crystallinity on the drug product surface. The use of process analytical technologies (PAT), including near infrared (NIR) and Raman spectroscopy, was evaluated, to predict the amorphous content, qualitatively and quantitatively, within itraconazole-loaded formulations. Calibration models were developed using partial least squares (PLS) regression, which successfully predicted amorphous content across the range of 0-20% w/w. The models demonstrated excellent linearity (R2 = 0.998 and 0.998) and accuracy (RMSEP = 1.04% and 0.63%) for NIR and Raman spectroscopy models, respectively. Overall, this article demonstrates the feasibility of SLS 3D printing to produce solid dispersions containing a BCS II drug, and the potential for NIR and Raman spectroscopy to quantify amorphous content as a non-destructive quality control measure at the point-of-care.

3D Printing of Tunable Zero-Order Release Printlets.

Zero-order release formulations are designed to release a drug at a constant rate over a prolonged time, thus reducing systemic side effects and improving patience adherence to the therapy. Such formulations are traditionally complex to manufacture, requiring multiple steps. In this work, fused deposition modeling (FDM) 3D printing was explored to prepare on-demand printlets (3D printed tablets). The design includes a prolonged release core surrounded by an insoluble shell able to provide zero-order release profiles. The effect of drug loading (10, 25, and 40% w/w paracetamol) on the mechanical and physical properties of the hot melt extruded filaments and 3D printed formulations was evaluated. Two different shell 3D designs (6 mm and 8 mm diameter apertures) together with three different core infills (100, 50, and 25%) were prepared. The formulations showed a range of zero-order release profiles spanning 16 to 48 h. The work has shown that with simple formulation design modifications, it is possible to print extended release formulations with tunable, zero-order release kinetics. Moreover, by using different infill percentages, the dose contained in the printlet can be infinitely adjusted, providing an additive manufacturing route for personalizing medicines to a patient.

Non-destructive dose verification of two drugs within 3D printed polyprintlets.

Three-dimensional printing (3DP) is a revolutionary technology in pharmaceuticals, enabling the personalisation of flexible-dose drug products and 3D printed polypills (polyprintlets). A major barrier to entry of this technology is the lack of non-destructive quality control methods capable of verifying the dosage of multiple drugs in polyprintlets at the point of dispensing. In the present study, 3D printed films and cylindrical polyprintlets were loaded with flexible, therapeutic dosages of two distinct drugs (amlodipine and lisinopril) across concentration ranges of 1-5% w/w and 2-10% w/w, respectively. The polyprintlets were non-destructively analysed for dose content using a portable near infrared (NIR) spectrometer and validated calibration models were developed using partial least squares (PLS) regression, which showed excellent linearity (R2 Pred = 0.997, 0.991), accuracy (RMSEP = 0.24%, 0.24%) and specificity (LV1 = 82.77%, 79.55%) for amlodipine and lisinopril, respectively. X-ray powder diffraction (XRPD) and thermogravimetric analysis (TGA) showed that sintering partially transformed the phase of both drugs from the crystalline to amorphous forms. For the first time, we report a non-destructive method for quality control of two separate active ingredients in a single 3D printed drug product using NIR spectroscopy, overcoming a major barrier to the integration of 3D printing into clinical practice.

3D printed drug products: Non-destructive dose verification using a rapid point-and-shoot approach.

Three-dimensional printing (3DP) has the potential to cause a paradigm shift in the manufacture of pharmaceuticals, enabling personalised medicines to be produced on-demand. To facilitate integration into healthcare, non-destructive characterisation techniques are required to ensure final product quality. Here, the use of process analytical technologies (PAT), including near infrared spectroscopy (NIR) and Raman confocal microscopy, were evaluated on paracetamol-loaded 3D printed cylindrical tablets composed of an acrylic polymer (Eudragit L100-55). Using a portable NIR spectrometer, a calibration model was developed, which predicted successfully drug concentration across the range of 4-40% w/w. The model demonstrated excellent linearity (R2 = 0.996) and accuracy (RMSEP = 0.63%) and results were confirmed with conventional HPLC analysis. The model maintained high accuracy for tablets of a different geometry (torus shapes), a different formulation type (oral films) and when the polymer was changed from acrylic to cellulosic (hypromellose, HPMC). Raman confocal microscopy showed a homogenous drug distribution, with paracetamol predominantly present in the amorphous form as a solid dispersion. Overall, this article is the first to report the use of a rapid 'point-and-shoot' approach as a non-destructive quality control method, supporting the integration of 3DP for medicine production into clinical practice.

Surface Chemistry and Humidity in Powder Electrostatics: A Comparative Study between Tribocharging and Corona Discharge.

In the present study, the correlation between surface chemical groups and the electrostatic properties of particulate materials was studied. Glass beads were modified to produce OH-, NH2-, CN-, and F-functionalized materials. The materials were charged separately both by friction and by conventional corona charging, and the results were compared. The results obtained from both methods indicated that the electrostatic properties are directly related to the surface functional group chemistry, with hydrophobic groups accumulating greater quantities of charge than hydrophilic groups. The fluorine-rich surface accumulated 5.89 times greater charge upon tribocharging with stainless steel than the hydroxyl-rich surface. However, in contrast to the tribocharging method, the charge polarity could not be determined when corona charging was used. Moreover, discharge profiles at different humidity levels (25% RH, 50% RH, and 75% RH) were obtained for each modified surface, which showed that higher humidity facilitates faster charge decay; however, this enhancement is surface chemistry-dependent. By increasing the humidity from 25% RH to 75% RH, the charge relaxation times can be accelerated 1.6 times for fluorine and 12.2 times for the cyano group. These data confirm that surface functional groups may dictate powder electrostatic behavior and account for observed charge accumulation and discharge phenomena.

Quantification of Tribocharging of Pharmaceutical Powders in V-Blenders: Experiments, Multiscale Modeling, and Simulations.

Pharmaceutical powders are very prone to electrostatic charging by colliding and sliding contacts. In pharmaceutical formulation processes, particle charging is often a nuisance and can cause problems in the manufacture of products, such as affecting powder flow, fill, and dose uniformity. For a fundamental understanding of the powder triboelectrification, it is essential to study charge transfer under well-defined conditions. Hence, all experiments in the present study were conducted in a V-blender located inside a glove box with a controlled humidity of 20%. To understand tribocharging, different contact surfaces, namely aluminum, Teflon, poly methyl methacrylate, and nylon were used along with 2 pharmaceutical excipients and 2 drug substances. For the pharmaceutical materials, the work function values were estimated using MOPAC, a semiempirical molecular orbital package which has been previously used for the solid-state studies and molecular structure predictions. For a mechanistic understanding of tribocharging, a discrete element model incorporating charge transfer and electrostatic forces was developed. An effort was made to correlate tribocharging of pharmaceutical powders to properties such as cohesive energy density and surface energy. The multiscale model used is restricted as it considers only spherical particles with smooth surfaces. It should be used judiciously for other experimental assemblies because it does not represent a full validation of a tightly integrated model.

West Midlands Health Informatics Network: A Perspective on Education and Training Needs.

The growth of health informatics as a discipline has led to an increase in networks of people with similar interests for discussion, learning and sharing. Alongside these community networks, education and training are gaining interest, with more career opportunities and general public seeking information. This paper highlights the experience of the West Midlands Health Informatics Network and efforts in better understanding the educational and training needs of its members. The findings from the survey conducted reveal that while the interest in this field is high among network members, the awareness of opportunities for training and learning professionally as well as personally, remains low. The areas and levels of interest in the region should help support the creation and availability of resources.

Development and testing of solid dose formulations containing polysialic acid insulin conjugate: next generation of long-acting insulin.

BACKGROUND: The need for lifelong, daily insulin injections can have a dramatic effect on patient compliance, can be painful, and runs the risk of local infections. Furthermore, needle-stick injuries are common, and the issue of needle disposal is troublesome. Injecting a long-acting insulin analog with needle-free administration would be a significant improvement for diabetic subjects, but is not currently feasible. To achieve a constant, reliable delivery of a novel, long-acting insulin analog, Lipoxen's SuliXen (polysialylated insulin) in a solid dosage form capable of being delivered without a needle has been developed. The aim of this study was to evaluate the feasibility of Lipoxen's SuliXen delivery with the Glide solid dose injector, Glide SDI. MATERIALS AND METHODS: A formulation containing 14 kDa polysialic acid (PSA)-recombinant human insulin conjugate was manufactured at Lipoxen PLC and transferred to Glide Pharma. The PSA-insulin conjugate solution was incorporated into different excipients at Glide Pharma (excipients 1 and 2), and formulations were manufactured containing implants with doses of 0.3 and 1.0 IU of insulin, respectively. Two different polymeric excipients were investigated for their suitable release profiles. The physicomechanical properties of the formulations were characterized in terms of solid dosage form strength (via three-point bend and compression) and disintegration time at 37 degrees C. A preclinical efficacy study was performed in a nondiabetic rat model (Sprague-Dawley). RESULTS: The study demonstrated successful incorporation of PSA-insulin conjugate into formulations compatible for use with the solid dose injector. Physicochemical characterization indicated that each formulation produced was physically robust. For excipient 1, the compressive stress and three-point-bend-test values recorded for the 0.3 IU formulation were 106.99 +/- 14.3 MPa and 30.6 +/- 1.4 N (force in newtons), respectively. Corresponding values for the 1.0 IU dose were 53.10 +/- 10.2 MPa and 16.66 +/- 1.0 N. For excipient 2, the compressive stress and three-point-bend-test values recorded for the 0.3 IU dose were 53.10 +/- 10.2 MPa and 7.64 +/- 0.9 N, respectively, whereas the corresponding values recorded for the 1.0 IU dose were 41.61 +/- 7.4 MPa and 13.18 +/- 1.3 N. Each formulation successfully penetrated a laboratory substrate, achieving 100% penetration in each case. In vivo analysis demonstrated that PSA-insulin conjugate shows prolongation of activity (at least two-fold more compared to insulin) for more than 5 hours in the rat model. CONCLUSION: Even though additional work may be required, for example, to develop several fixed dose formulations, the preliminary results show that solid dosage forms incorporating PSA-insulin conjugate maintained the prolongation of PSA-insulin conjugate activity in the rat model. Convenient and easy to use, the solid dose injector will not only ensure diabetic patient compliance and trust but also provide cost-effective solutions for safe, reliable, and controlled needle-free injection of PSA-insulin conjugate.