Modeling of Styl'One Evolution Correction Factors for Multicomponent Mixtures Scaling-up to Roller Compaction.

Roll compaction (RC) is a cost-effective dry granulation method, widely implemented in the pharmaceutical industry. In early formulation development however, when the material availability is limited, being able to predict the most important parameters in RC, like gap width and specific compaction force (SCF), to obtain a target ribbon solid fraction (SF) would significantly improve the formulation development efficiency as it would avoid the need of performing experiments on the roller compactor itself. However, at the present state of things, experiments on RC mechanical simulators present an overestimation of the target SF, when compared to roller compactor SF values. Although numerous correction approaches have been developed to improve the predictive performance of different mathematical models applied to the simulation experimental results, no study has collected a database wide enough to demonstrate the validity of a correction factor that allows to accurately simulate the compaction behavior of multicomponent mixtures. Here, 25 different formulations at 40 % drug load are compacted at different SCFs, both on a RC mimicking device (Styl'One Evolution) and on an actual roller compactor (Gerteis Mini-Pactor): following a similar approach as Reimer et al. and implementing a simplified version of the Johanson's mathematical model, 4 different correction factors are calculated, depending on how their material properties and pressure dependencies are considered. In conclusion, one correction factor is identified as the optimal trade-off between the SF prediction accuracy on the Gerteis Mini-Pactor and its applicability to a wide range of formulations, as it is independent of the material properties. This finding is particularly relevant when applied to scale-up to this specific roller compactor or early development processes of new formulations that have not been mechanically characterized yet.

Current State of Minitablet Product Design: A Review.

Interest in minitablets (MTs) has grown exponentially over the last 20 years and especially the last decade, as evidenced by the number of publications cited in Scopus and PubMed. MTs offer significant opportunities for personalized medicine, dose titration and flexible dosing, taste masking, and customizing drug delivery systems. Advances in specialized MT tooling, manufacturing, and characterization instrumentation have overcome many of the earlier development issues. Breakthrough MT swallowability, acceptability, and palatability research have challenged the long-standing idea that only liquids are acceptable dosage forms for infants and young children. MTs have been shown to be a highly acceptable dosage form for infants, small children, and geriatric patients who have difficulty swallowing. This review discusses the current state of MT applications, acceptability in pediatric and geriatric populations, medication adherence, manufacturing processes such as tableting and coating, running powder and tablet characterization, packaging and MT dispensing, and regulatory considerations.

3D-printed solid oral dosage forms for mental and neurological disorders: recent advances and future perspectives.

INTRODUCTION: 3D printing (3DP) applications in medicine are intensively investigated, creating an opportunity to provide patient-tailored therapy by delivering a drug with an accurate dose and release profile. Moving away from the 'one size fits all' paradigm, it could be beneficial for treating mental and neurological disorders, improving the efficiency and safety of the therapy. The aim of this critical review is to assess recent advances and identify gaps regarding 3DP in this important and challenging field, by focusing on recent research examples. AREAS COVERED: Applications of the 3DP techniques for solid dosage forms in mental and neurological disorders have been covered and discussed, together with recent advantages, limitations, and future directions. EXPERT OPINION: The personalize treatment, which is considered as the most significant advantage of the 3DP technique, can be beneficial in mental and neurological disorders therapy, where the dose should be adjusted to the patient. Printing of medicines enables creating the structure modifications and thus controlling the drug release or combining multiple drugs into one tablet, simplifying the dose regimen. Medications printed on-demand, in health-care facilities, could address the special needs of pediatric patients and help avoid interruptions in the supply chain. Despite promising advances, the described methods have limitations and need further investigation before being scaled-up to an industrial manufacturing environment. There is also a need to establish protocols for the preparation and registration of 3DP dosage forms.

Imaging techniques for studying solid dosage formulation: Principles and applications.

Classic methods for evaluating the disintegration and dissolution kinetics of solid dosage forms are no longer sufficient to meet the growing demands in the pharmaceutical field. Hence, scientists have turned to imaging techniques and computer technology to develop innovative visualization methods. These methods allow for a visual understanding of the disintegration or dissolution process and offer valuable insights into the drug release kinetics. This article aims to provide an overview of the commonly used imaging techniques and their applications in studying the disintegration or dissolution of solid dosage forms. Therefore, imaging presents a novel and alternative approach to understanding the mechanisms of disintegration and dissolution in the formulation study of solid dosages.

A comprehensive review on pharmaceutical excipients.

The effectiveness of pharmaceutical drugs depends not only on their active components and manufacturing processes, but also on the role played by pharmaceutical excipients. The traditional definition of excipients as inactive and cost-effective substances has evolved significantly. They are now recognized as essential elements of drug formulations, constituting 80-90% of the final product. The rapid advancements in delivery systems, along with scientific, regulatory, financial and technological developments in biopharmaceutics, have generated renewed interest in the use and functionality of excipients, especially in solid dosage forms. This review focuses on the categorization of excipients according to the International Pharmaceutical Excipient Council (IPEC) and the establishment of guidelines for evaluating the safety of a new proposed excipient.

Excipients are matter we add to medicine when we make it. They give the medicine different qualities, like making it easier to dissolve, stick together, or slide smoothly. But if we use too many excipients, it can make the medicine less stable and more expensive. To avoid these problems, we can use special excipients that can do more than one thing. These multi-purpose excipients make the medicine work better, stay stable and cost less.

The effect of particle size on the sublimation behavior of butylhydroxytoluene as antioxidant in tablets during storage and coating.

The effect of particle size on the sublimation behavior of butylhydroxytoluene (BHT) was investigated when BHT was included as antioxidant in tablets. Sublimation of pure BHT was found to be independent of its particle size, with pore formation on the surface of all tablets after storage at room temperature and above. Moreover, a higher residual BHT content after storage was detected in tablets containing a larger size fraction. X-ray µCT scans revealed the formation of peripherally larger pores at higher BHT particle sizes, implying a slower sublimation rate in the tablet core. A stability study indicated an increase in the extent of BHT sublimation at higher temperature and longer exposure time for all size fractions. The influence of BHT particle size was more pronounced when the tablets were stored at higher temperature, but the effect receded with longer exposure time. Similar trends were seen in film-coated tablets. Due to the short exposure time to elevated temperatures, a gradient in pore size was also observed at smaller particle sizes, with peripheral pores being larger in uncoated tablets. Superficial pores disappeared when a film coating was deposited onto the tablets. After storage of the film-coated tablets, less BHT had sublimated compared to the uncoated tablet. The coating layer did not prevent sublimation, but the process was slowed down.

3D Printing Technology as a Promising Tool to Design Nanomedicine-Based Solid Dosage Forms: Contemporary Research and Future Scope.

3D printing technology in medicine is gaining great attention from researchers since the FDA approved the first 3D-printed tablet (Spritam®) on the market. This technique permits the fabrication of various types of dosage forms with different geometries and designs. Its feasibility in the design of different types of pharmaceutical dosage forms is very promising for making quick prototypes because it is flexible and does not require expensive equipment or molds. However, the development of multi-functional drug delivery systems, specifically as solid dosage forms loaded with nanopharmaceuticals, has received attention in recent years, although it is challenging for formulators to convert them into a successful solid dosage form. The combination of nanotechnology with the 3D printing technique in the field of medicine has provided a platform to overcome the challenges associated with the fabrication of nanomedicine-based solid dosage forms. Therefore, the major focus of the present manuscript is to review the recent research developments that involved the formulation design of nanomedicine-based solid dosage forms utilizing 3D printing technology. Utilization of 3D printing techniques in the field of nanopharmaceuticals achieved the successful transformation of liquid polymeric nanocapsules and liquid self-nanoemulsifying drug delivery systems (SNEDDS) to solid dosage forms such as tablets and suppositories easily with customized doses as per the needs of the individual patient (personalized medicine). Furthermore, the present review also highlights the utility of extrusion-based 3D printing techniques (Pressure-Assisted Microsyringe-PAM; Fused Deposition Modeling-FDM) to produce tablets and suppositories containing polymeric nanocapsule systems and SNEDDS for oral and rectal administration. The manuscript critically analyzes contemporary research related to the impact of various process parameters on the performance of 3D-printed solid dosage forms.

Influence of formulation variables on the processability and properties of tablets manufactured by fused deposition modelling.

The present work studied the influence of different formulation variables (defined also as factors), namely, different polymers (HPC EF, PVA and HPMC-AS LG), drugs with different water solubilities (paracetamol, hydrochlorothiazide and celecoxib) and drug loads (10 or 30 %) on their processability by HME and FDM. Both filaments and tablets were characterized for physic and chemical properties (DSC, XRPD, FTIR) and performance properties (drug content, in vitro drug release). Experiments were designed to highlight relationships between the 3 factors selected and the mechanical properties of filaments, tablet mass and dissolution profiles of the model drugs from printed tablets. While the combination of hydrochlorothiazide and HPMC-AS LG could not be extruded, the combination of paracetamol with HPC EF turned the filaments too ductile and not stiff enough hampering the process of printing. All other polymer and drug combinations could be successfully extruded and printed. Models reflected the influence of the solubility of the drug considered but not the drug load in formulations. The ranking of the drug release rates was in good agreement with their solubilities. Furthermore, PVA presenting the fastest swelling rate, promoted the fastest drugs' releases in comparison with the other polymers studied. Overall, the study enabled the identification of the key factors affecting the properties of printed tablets, with the proposal of a model that has valued the relative contribution of each factor to the overall performance of tablets.

Solid state 13C NMR spectroscopy as a tool for identification of counterfeit Viagra tablets and guide for develop new identification approach of falsified product.

Counterfeit drugs are a global problem that is directly related to the safety and effectiveness of pharmacotherapy. The black market for counterfeit products is constantly growing and related to the wide availability through online shopping. Therefore, there is a constant need to develop analytical methods that would allow for the unambiguous identification of counterfeit products from the original ones. One of such techniques is solid-state NMR spectroscopy, which allows for direct registration and analysis of spectra of multicomponent solid forms of pharmaceutical formulations. The paper explores the possibility of using this technique in the identification of counterfeit Viagra tablets. In this study, solid-state NMR has been used to detect the non-pharmacopoeial cellulose present in the samples of counterfeit Viagra tablets. Besides, the NMR results allowed to develop a rapid dying technique that can be used to distinguish between the counterfeit and original drug. It has been shown that solid-state NMR spectroscopy allows for numerous analyses such as identification of counterfeit products, assessment of the composition of analyte, estimation of qualitative differences between the original and falsified product, and the development of simple analytical methods based on tablets composition differences.

Hybrid Manufacturing of Oral Solid Dosage Forms via Overprinting of Injection-Molded Tablet Substrates.

Since 3D printing allows for patient-specific dosage forms, it has become a major focus in pharmaceutical research. However, it is difficult to scale up drug product manufacturing. Injection molding has been used in conjunction with hot-melt extrusion to mass produce drug products, but making tailored solid dosage forms with this technology is neither cost-effective nor simple. This study explored the use of a combination of fused filament fabrication and injection molding to create patient-specific solid dosage forms. A tablet fixation and location template was used to overprint directly on injection-molded tablet bases, and theophylline was combined with polycaprolactone and Kollidon® VA64 via hot-melt extrusion to produce the filament. Dynamic mechanical analysis was used to evaluate the brittleness of the filament, and differential scanning calorimetry was used to analyze the thermal results. The results showed that theophylline had a flow promoting effect on the polymer blend and that overprinted tablets were manufactured faster than 3D-printed tablets. Drug release studies also showed that overprinted tablets released faster than injection-molded tablets. This method demonstrates the potential of hybrid manufacturing for the pharmaceutical industry as a means of bridging the gap between personalized dosage forms and mass production.

Coating of Primary Powder Particles Improves the Quality of Binder Jetting 3D Printed Oral Solid Products.

Binder jetting (BJ) 3D printing is especially suitable for the fabrication of an orodispersible solid dosage form, as it is an efficient way to avoid the use of mechanical forces typical for compaction-based processes. However, one of the existing challenges related to pharmaceutical applications of BJ is the relatively high amount of binder needed in the primary powder to ensure the sufficient mechanical strength of printed products. In this study, a strategy based on pre-processing with a thin layer coating was explored. With this strategy, the matrix particles (lactose monohydrate) of the primary powder for BJ 3D printing were coated with the binder (polyvinylpyrrolidone, PVP). The investigated compositions of the primary powder contained PVP at three levels, namely, 10 %, 15% and 20% (w/w). The primary powder compositions were prepared with or without the coated lactose powder, and they were subsequently 3D BJ printed into oral solid products with paracetamol as a model active drug substance. The presence of coated lactose in the primary powder increased the interparticulate interactions in the BJ 3D printed products. Especially for the composition with a relatively small amount of binder (i.e., 10% and 15% w/w PVP in the primary powder), the use of coated particles significantly improved the resistance to crushing and decreased the disintegration time of printed products. In conclusion, thin layer coating is an effective way to pre-process primary powder particles for BJ 3D printing of oral solid products.

Micro-viscoelastic Characterization of Compressed Oral Solid Dosage Forms with Ultrasonic Wave Dispersion Analysis.

Due to their constituent powders, the materials of advanced compressed oral solid dosage (OSD) forms are micro-composites and strongly visco-elastic at macro- and micro-length scales. The disintegration, drug release, and mechanical strength of OSD forms depend on its micro-texture (such as porosity) and micro-scale physical/mechanical properties. In the current work, an algorithmic ultrasonic characterization framework for extracting the micro-visco-elastic properties of OSD materials is presented, and its applicability is demonstrated with a model material. The proposed approach is based on the effect of visco-elasticity and granularity on the frequency-dependent attenuation of an ultrasonic wave pulse in a composite (granular) and viscous medium. In modeling the material, a two-parameter Zener model for visco-elasticity and a scattering attenuation mechanism based on Rayleigh scattering for long-wave approximation are employed. A novel linear technique for de-coupling the effects of micro-visco-elasticity and scattering on attenuation and dispersion is developed and demonstrated. The apparent Young's modulus, stress, and strain relaxation time constants of the medium at micro-scale are extracted and reported. Based on this modeling and analysis framework, a set of computational algorithms has been developed and demonstrated with experimental data, and its practical utility in pharmaceutical manufacturing and real-time release testing of tablets is discussed.

Evaluating Spatially Offset Low-Frequency Anti-Stokes Raman Spectroscopy (SOLFARS) for Detecting Subsurface Composition below an Emissive Layer: A Proof of Principle Study Using a Model Bilayer System.

This work explores the potential use of spatially offset low-frequency anti-Stokes Raman spectroscopy (SOLFARS) to detect subsurface composition below an emissive surface. A range of bilayer tablets were used to evaluate this approach. Bilayer tablets differed in both the underlying layer composition (active pharmaceutical ingredient to excipient ratio, celecoxib: α-lactose monohydrate) and the upper layer thickness of the fluorescent coating (polyvinylpyrrolidone mixture with sunset yellow FCF dye). Two low- (<300 cm-1) plus mid- (300 to 1800 cm-1) frequency Raman instrumental setups, with lateral displacements for spatial analysis of solid dosage forms, using different excitation wavelengths were explored. The 532 nm system was used to illustrate how the low-frequency anti-Stokes Raman approach works with samples exhibiting extreme fluorescence/background emission interference, and the 785 nm system was used to demonstrate the performance when less extreme fluorescence/emission is present. Qualitative and quantitative chemometric analyses were performed to evaluate the performance of individual spectral domains and their combinations for the determination of the composition of the subsurface layer as well as the coating layer thickness. Overall, the commonly used midfrequency region (300-1800 cm-1) proved superior when using 785 nm incident laser for quantifying the coating thickness (amorphous materials), whereas a combined Stokes and anti-Stokes low-frequency region was found to be superior for quantifying underlying crystalline materials. When exploring individual spectral regions for subsurface composition using spatially offset measurements, the anti-Stokes LFR spectral window performed best. The anti-Stokes low-frequency range also demonstrated an advantage for models composed of data exhibiting high levels of fluorescence (e.g., data collected using 532 nm incident laser), as the Stokes scattering was masked by fluorescence. Transmission measurements were also explored for comparison and showed the best applicability for both upper and lower layer analysis, attributed to the inherently larger bulk sampling volume of this setup. From a practical perspective, these results highlight the potential adjustments that can be made to already existing (in-line) Raman setups to facilitate similar analysis in pharmaceutical industry-based settings.

Are There Differences in the Homogeneity of the Parts of Tablets Obtained after Subdivision?-A Preliminary Assessment Using an X-ray Microtomography.

Aim: The study aimed to analyze the weight and homogeneity of the parts of tablets containing carbamazepine and tablets with trazodone hydrochloride, obtained after subdivision with a kitchen knife. X-ray microtomography was used for homogeneity analysis. Methods: 30 tablets with carbamazepine and 30 tablets with trazodone hydrochloride were analyzed in terms of weight uniformity after subdivision. Then, seven tablets of each type were analyzed using an X-ray microtomography (Phoenix vǀtomeǀx, General Electric). The absorption of X-rays by an object is proportional to its density. In turn, measurement of the density of the analyzed object in a microtomographic image is the grayscale level. Based on the correlation between the grayscale value and the reference density, from the calibration phantom, we were able to determine the density of any area of the tablet's scan. Results: During the subdivision, the weight loss exceeded 3% for two carbamazepine tablets, while for trazodone tablets, none lost more than 3%, which is the limit recommended by Food and Drug Administration (FDA). As to the density of the tablets resulting from the microtomographic analysis, two of the whole tablets containing trazodone hydrochloride had a significantly higher density than the remainder (p < 0.001). Similarly, some differences in density were observed in the analysis of the density of tablets of carbamazepine (p = 0.008). Parts of one of the analyzed tablets with trazodone obtained after subdivision differed in terms of pixel brightness, thus density. On the other hand, the uniform density was observed for parts of the split tablets containing carbamazepine. Conclusions: Parts of the trazodone hydrochloride tablets obtained after subdivision differed in terms of homogeneity and weight. Microtomographic methods may be an interesting and useful method for evaluating the uniformity of compounds in solid dosage forms.

Effect of shape on the physical properties of pharmaceutical tablets.

Despite a well-established process understanding, quality issues for compressed oral solid dosage forms are frequently encountered during various drug product development and production stages. In the current work, a non-destructive contact ultrasonic experimental rig integrated with a collaborative robot arm and an advanced vision system is presented and employed to quantify the effect of the shape of a compressed tablet on its mechanical properties. It is observed that these properties are affected by the tablet geometric shapes and found to be linearly sensitive to the compaction pressures. It is demonstrated that the presented approach significantly improves the repeatability of the experimental waveform acquisition. In addition, with the increased confidence levels in waveform acquisition accuracy and corresponding pressure and shear wave speeds due to improved measurement repeatability, we conclude that pharmaceutical compact materials can indeed have a negative Poisson's ratio, therefore can be auxetic. The presented technique and instrument could find critical applications in continuous tablet manufacturing, and its real-time quality monitoring as measurement repeatability has been significantly improved, minimizing product quality variations.

Preparation of oral solid dosage forms based on homogenized spot melting technique.

Given the benefits of high printing precision and capability, the selective laser sintering technique has been used to manufacture medicines and implants with unique engineering and functional properties. Using homogenized beams with a reduced thermal gradient and a larger diameter as an alternative energy source, the thermal stability and production efficiency of powder bed fusion would be improved. Herein, a novel homogenized spot melting (HSM) technology for pharmaceutical preparation was developed in this study. The melting behavior of typical pharmaceutical polymers under a homogenized spot was determined. A crystalline polymer with a low melting point was used as a solid binder, and the HSM printability and formation of drug-loaded formulations were explored. Oral solid dosage forms with different morphological and dissolution designs were prepared and evaluated under optimal formulation and process conditions. It was observed that HSM reduced the surface temperature distribution of the powder bed and improved the printability of drugs and excipients. Crystalline PEG 8000 with suitable flowability and heat conduction efficiency in the molten state was preferable for HSM printing. Incorporating 40% PEG 8000 as a solid binder was an effective strategy for HSM processing of unfused or unstable powders. Solid preparations with different structures and dissolution behaviors were successfully printed, suggesting that HSM is a promisingtechnique for personalized medicine.

Ensuring Product Stability - Choosing the Right Excipients.

The stability of pharmaceuticals is an important product quality attribute. Of the known factors affecting stability, moisture is often perceived as the most common cause of drug degradation by hydrolysis or other reactions facilitated by moisture as a medium. Excipients are a critical entity in formulations to enable drug delivery as well as efficient manufacture of pharmaceutical dosage forms. Yet to this end, there is limited application and understanding of the role of excipients in protecting moisture sensitive drugs. An improved understanding of moisture-excipient interactions is important when selecting excipients for formulations containing moisture sensitive drugs. This review outlines the role of excipients as a moisture protectant in oral solid dosage forms. It focuses on the moisture interactions of excipients in order to highlight the potential of certain excipients as moisture protectants. More specifically, the mechanisms by which excipients can reduce drug degradation (e.g. acting as a physical barrier, reducing moisture availability and mobility) are discussed. A summary of analytical tools to evaluate moisture-excipient interactions is also provided.

Stabilizing vaccines via drying: Quality by design considerations.

Pandemics and epidemics are continually challenging human beings' health and imposing major stresses on the societies particularly over the last few decades, when their frequency has increased significantly. Protecting humans from multiple diseases is best achieved through vaccination. However, vaccines thermal instability has always been a hurdle in their widespread application, especially in less developed countries. Furthermore, insufficient vaccine processing capacity is also a major challenge for global vaccination programs. Continuous drying of vaccine formulations is one of the potential solutions to these challenges. This review highlights the challenges on implementing the continuous drying techniques for drying vaccines. The conventional drying methods, emerging technologies and their adaptation by biopharmaceutical industry are investigated considering the patented technologies for drying of vaccines. Moreover, the current progress in applying Quality by Design (QbD) in each of the drying techniques considering the critical quality attributes (CQAs), critical process parameters (CPPs) are comprehensively reviewed. An expert advice is presented on the required actions to be taken within the biopharmaceutical industry to move towards continuous stabilization of vaccines in the realm of QbD.

Seeing Is Believing: Time-Lapse Macro-Imaging of Morphological Changes of Solid Dosages as a Teaching and Research Tool.

PURPOSE: Disintegration kinetics and behaviors are critical for the quality and performance of oral solid dosages. Instead of performing standard disintegration tests, herein, we aim to visualize these kinetic processes in real time. METHOD: A visual acquisition system is developed to capture the morphological changes of tablets under static conditions via time-lapse macro-imaging. The system consists of: i) a customized quartz chamber, ii) a metal sieve with pore sizes ranging from 1 to 2 mm in diameter to allow rapid settling of the disintegrated particles, and iii) a temperature-controlled water bath. A typical workflow consists of the following steps: i) planning of the experiment to consider the type of the active pharmaceutical ingredient and drug release mechanism; ii) acquisition of photo-imaging data from at least two cameras arranged at different angles over a predetermined time period; iii) post-processing of the image data; iv) production of video clips and image analysis. RESULTS: Representative works are shown to demonstrate the disintegration phenomenon or the morphological changes of solid drug products of various controlled- and extended-release mechanisms. CONCLUSION: These video clips are used as teaching materials for students majoring in pharmacy or pharmaceutical chemistry, which also provide an insightful unique perspective of the microprocess during tablet fragmentation, disintegration or drug release.

Application and Multi-Stage Optimization of Daylight Polymer 3D Printing of Personalized Medicine Products.

Additive technologies have undoubtedly become one of the most intensively developing manufacturing methods in recent years. Among the numerous applications, the interest in 3D printing also includes its application in pharmacy for production of small batches of personalized drugs. For this reason, we conducted multi-stage pre-formulation studies to optimize the process of manufacturing solid dosage forms by photopolymerization with visible light. Based on tests planned and executed according to the design of the experiment (DoE), we selected the optimal quantitative composition of photocurable resin made of PEG 400, PEGDA MW 575, water, and riboflavin, a non-toxic photoinitiator. In subsequent stages, we adjusted the printer set-up and process parameters. Moreover, we assessed the influence of the co-initiators ascorbic acid or triethanolamine on the resin's polymerization process. Next, based on an optimized formulation, we printed and analyzed drug-loaded tablets containing mebeverine hydrochloride, characterized by a gradual release of active pharmaceutical ingredient (API), reaching 80% after 6 h. We proved the possibility of reusing the drug-loaded resin that was not hardened during printing and determined the linear correlation between the volume of the designed tablets and the amount of API, confirming the possibility of printing personalized modified-release tablets.